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1
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Fines C, McCarthy H, Buckley N. The search for a TNBC vaccine: the guardian vaccine. Cancer Biol Ther 2025; 26:2472432. [PMID: 40089851 PMCID: PMC11913391 DOI: 10.1080/15384047.2025.2472432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 02/18/2025] [Accepted: 02/19/2025] [Indexed: 03/17/2025] Open
Abstract
Nearly 20 million people are diagnosed with cancer each year with breast cancer being the most common among women. Triple negative breast cancer (TNBC), defined by its no/low expression of ER and PR and lack of amplification of HER2, makes up 15-20% of all breast cancer cases. While patients overall have a higher response to chemotherapy, this subgroup is associated with the lowest survival rate indicating significant clinical and molecular heterogeneity demanding alternate treatment options. Therefore, new therapies have been explored, with a large focus on utilizing the immune system. A whole host of immunotherapies have been studied including immune checkpoint inhibitors, now standard of care for eligible patients, and possibly the most exciting and promising is that of a TNBC vaccine. While currently there are no approved TNBC vaccines, this review highlights many promising studies and points to an antigen, p53, which we believe is highly relevant for TNBC.
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Affiliation(s)
- Cory Fines
- School of Pharmacy, Queen’s University Belfast, Belfast, UK
| | - Helen McCarthy
- School of Pharmacy, Queen’s University Belfast, Belfast, UK
| | - Niamh Buckley
- School of Pharmacy, Queen’s University Belfast, Belfast, UK
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2
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Cai BH, Chen CC, Sung YT, Shih YC, Lien CF. Strategies for Anticancer Treatment in p53-Mutated Head and Neck Squamous Cell Carcinoma. Biomedicines 2025; 13:1165. [PMID: 40426992 PMCID: PMC12108584 DOI: 10.3390/biomedicines13051165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 04/24/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
This Opinion summarizes the strategies for anticancer treatment in p53-mutated head and neck squamous cell carcinoma (HNSCC). It examines six strategies for anticancer treatment in p53-mutated HNSCC: 1. direct reactivation of mutated p53; 2. activation of p63; 3. activation of p73; 4. degradation of mutated p53; 5. blocking the p53-regulated oncogenic microRNA; and 6. blocking the p53-regulated oncogenic long non-coding RNA. Since HNSCC has a high p53 mutation rate compared to other types of cancers, these strategies for combating p53-mutated HNSCC may prove useful for generating new ideas or methods for developing treatments for other cancers with p53 mutations. This article also explores other factors that may impact the effectiveness of anticancer therapies in p53-mutated HNSCC.
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Affiliation(s)
- Bi-He Cai
- School of Medicine, I-Shou University, Kaohsiung City 82445, Taiwan
| | - Chia-Chi Chen
- School of Medicine, I-Shou University, Kaohsiung City 82445, Taiwan
- Department of Pathology, E-Da Hospital, Kaohsiung City 82445, Taiwan;
| | - Yu-Te Sung
- Department of Plastic Surgery, E-Da Hospital, Kaohsiung City 82445, Taiwan;
| | - Yu-Chen Shih
- Department of Otolaryngology-Head and Neck Surgery, E-Da Hospital, Kaohsiung City 82445, Taiwan;
| | - Ching-Feng Lien
- School of Medicine, I-Shou University, Kaohsiung City 82445, Taiwan
- Department of Otolaryngology-Head and Neck Surgery, E-Da Hospital, Kaohsiung City 82445, Taiwan;
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Skrabalak I, Rajtak A, Malachowska B, Skrzypczak N, Skalina KA, Guha C, Kotarski J, Okla K. Therapy resistance: Modulating evolutionarily conserved heat shock protein machinery in cancer. Cancer Lett 2025; 616:217571. [PMID: 39986370 DOI: 10.1016/j.canlet.2025.217571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 02/16/2025] [Accepted: 02/17/2025] [Indexed: 02/24/2025]
Abstract
Therapy resistance is a major barrier to achieving a cure in cancer patients, often resulting in relapses and mortality. Heat shock proteins (HSPs) are a group of evolutionarily conserved proteins that play a prominent role in the progression of cancer and drug resistance. HSP synthesis is upregulated in cancer cells, facilitating adaptation to various tumor microenvironment (TME) stressors, including nutrient deprivation, exposure to DNA-damaging agents, hypoxia, and immune responses. In this review, we present background information about HSP-mediated cancer therapy resistance. Within this context, we emphasize recent progress in the understanding of HSP machinery, exploring the therapeutic potential of HSPs in cancer treatment.
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Affiliation(s)
- Ilona Skrabalak
- The First Department of Oncologic Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland
| | - Alicja Rajtak
- The First Department of Oncologic Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland; IOA, 3 Lotnicza St, 20-322 Lublin, Poland
| | - Beata Malachowska
- Department of Radiation Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Natalia Skrzypczak
- Department of Pathology and Clinical Laboratories, University of Michigan, Ann Arbor, MI, USA
| | - Karin A Skalina
- Department of Radiation Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Chandan Guha
- Department of Radiation Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Jan Kotarski
- The First Department of Oncologic Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland
| | - Karolina Okla
- Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA; IOA, 3 Lotnicza St, 20-322 Lublin, Poland.
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4
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Isermann T, Schneider KL, Wegwitz F, De Oliveira T, Conradi LC, Volk V, Feuerhake F, Papke B, Stintzing S, Mundt B, Kühnel F, Moll UM, Schulz-Heddergott R. Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition. Cell Death Differ 2025:10.1038/s41418-025-01502-x. [PMID: 40204953 DOI: 10.1038/s41418-025-01502-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 03/04/2025] [Accepted: 03/21/2025] [Indexed: 04/11/2025] Open
Abstract
The stress-associated chaperone system is an actionable target in cancer therapies. It is ubiquitously upregulated in cancer tissues and enables tumorigenicity by stabilizing oncoproteins. Most inhibitors target the key component, heat-shock protein 90 (HSP90). Although HSP90 inhibitors are highly tumor-selective, they fail in clinical trials. These failures are partly due to interference with a negative regulatory feedback loop in the heat-shock response (HSR): in response to HSP90 inhibition, there is compensatory synthesis of stress-inducible chaperones, mediated by the transcription factor heat-shock-factor 1 (HSF1). We recently identified that wild-type p53 reduces the HSR by repressing HSF1 via a p21-CDK4/6-MAPK-HSF1 axis. Here, we test whether in HSP90-based therapies, simultaneous p53 activation or direct cell cycle inhibition interrupts the deleterious HSF1-HSR axis and improves the efficiency of HSP90 inhibitors. We found that the clinically relevant p53 activator Idasanutlin suppresses the HSF1-HSR activity in HSP90 inhibitor-based therapies. This combination synergistically reduces cell viability and accelerates cell death in p53-proficient colorectal cancer (CRC) cells, murine tumor-derived organoids, and patient-derived organoids (PDOs). Mechanistically, upon combination therapy, CRC cells upregulate p53-associated pathways, apoptosis, and inflammatory pathways. Likewise, in a CRC mouse model, dual HSF1-HSP90 inhibition represses tumor growth and remodels immune cell composition. Importantly, inhibition of the cyclin-dependent kinases 4/6 (CDK4/6) under HSP90 inhibition phenocopies synergistic repression of the HSR in p53-proficient CRC cells. Moreover, in p53-deficient CRC cells, HSP90 inhibition in combination with CDK4/6 inhibitors similarly suppresses the HSF1-HSR and reduces cancer growth. Likewise, p53-mutated PDOs respond to dual HSF1-HSP90 inhibition, providing a strategy to target CRC independent of the p53 status. In sum, we provide new options to improve HSP90-based therapies to enhance CRC therapies.
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Affiliation(s)
- Tamara Isermann
- Department of Molecular Oncology, University Medical Center Göttingen, Göttingen, Germany
- Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
- German Cancer Consortium (DKTK); Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Kim Lucia Schneider
- Department of Molecular Oncology, University Medical Center Göttingen, Göttingen, Germany
| | - Florian Wegwitz
- Department of Gynecology and Obstetrics, University Medical Center Göttingen, Göttingen, Germany
| | - Tiago De Oliveira
- Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Lena-Christin Conradi
- Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Valery Volk
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | | | - Björn Papke
- Laboratory of Molecular Tumor Pathology and Systems Biology, Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany
- German Cancer Consortium (DKTK); Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sebastian Stintzing
- German Cancer Consortium (DKTK); Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Bettina Mundt
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Florian Kühnel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ute M Moll
- Department of Pathology, Stony Brook University, Stony Brook, NY, USA
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5
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Stewart M, Schisler JC. Targeting chaperone modifications: Innovative approaches to cancer treatment. J Biol Chem 2024; 300:107907. [PMID: 39433125 PMCID: PMC11599458 DOI: 10.1016/j.jbc.2024.107907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 10/09/2024] [Accepted: 10/15/2024] [Indexed: 10/23/2024] Open
Abstract
Cancer and other chronic diseases are marked by alterations in the protein quality control system, affecting the posttranslational destiny of various proteins that regulate, structure, and catalyze cellular processes. Cellular chaperones, also known as heat shock proteins (HSPs), are pivotal in this system, performing protein triage that often determines the fate of proteins they bind to. Grasping the regulatory mechanisms of HSPs and their associated cofactors is crucial for understanding protein quality control in both healthy and diseased states. Recent research has shed light on the interactions within the protein quality control system and how post-translational modification govern protein interactions, function, and localization, which can drive or inhibit cell proliferation. This body of work encompasses critical elements of the heat shock response, including heat shock protein 70, heat shock protein 90, carboxyl-terminus of HSC70 interacting protein, and heat shock protein organizing protein. This review aims to synthesize these advancements, offering a holistic understanding of the system and its response when commandeered by diseases like cancer. We focus on the mechanistic shift in co-chaperone engagement-transitioning from heat shock protein organizing protein to carboxyl-terminus of HSC70 interacting protein in association with heat shock protein 70 and heat shock protein 90-which could influence cellular growth and survival pathways. A comprehensive examination of posttranslational modification-driven regulation within the protein quality control network is presented, highlighting the roles of activation factors, chaperones, and co-chaperones. Our insights aim to inform new strategies for therapeutically targeting diseases by considering the entire heat shock response system.
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Affiliation(s)
- Mariah Stewart
- The McAllister Heart Institute and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jonathan C Schisler
- The McAllister Heart Institute and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; The Department of Pathology and Lab Medicine and Computational Medicine Program, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
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6
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Sebastian RM, Patrick JE, Hui T, Amici DR, Giacomelli AO, Butty VL, Hahn WC, Mendillo ML, Lin YS, Shoulders MD. Dominant-negative TP53 mutations potentiated by the HSF1-regulated proteostasis network. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.01.621414. [PMID: 39554167 PMCID: PMC11565964 DOI: 10.1101/2024.11.01.621414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Protein mutational landscapes are sculpted by the impacts of the resulting amino acid substitutions on the protein's stability and folding or aggregation kinetics. These properties can, in turn, be modulated by the composition and activities of the cellular proteostasis network. Heat shock factor 1 (HSF1) is the master regulator of the cytosolic and nuclear proteostasis networks, dynamically tuning the expression of cytosolic and nuclear chaperones and quality control factors to meet demand. Chronic increases in HSF1 levels and activity are prominent hallmarks of cancer cells. One plausible explanation for this observation is that the consequent upregulation of proteostasis factors could biophysically facilitate the acquisition of oncogenic mutations. Here, we experimentally evaluate the impacts of chronic HSF1 activation on the mutational landscape accessible to the quintessential oncoprotein p53. Specifically, we apply quantitative deep mutational scanning of p53 to assess how HSF1 activation shapes the mutational pathways by which p53 can escape cytotoxic pressure conferred by the small molecule nutlin-3, which is a potent antagonist of the p53 negative regulator MDM2. We find that activation of HSF1 broadly increases the fitness of dominant-negative substitutions within p53. This effect of HSF1 activation was particularly notable for non-conservative, biophysically unfavorable amino acid substitutions within buried regions of the p53 DNA-binding domain. These results indicate that chronic HSF1 activation profoundly shapes the oncogenic mutational landscape, preferentially supporting the acquisition of cancer-associated substitutions that are biophysically destabilizing. Along with providing the first experimental and quantitative insights into how HSF1 influences oncoprotein mutational spectra, these findings also implicate HSF1 inhibition as a strategy to reduce the accessibility of mutations that drive chemotherapeutic resistance and metastasis.
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Affiliation(s)
- Rebecca M. Sebastian
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Jessica E. Patrick
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Tiffani Hui
- Department of Chemistry, Tufts University, Medford, MA, USA
| | - David R. Amici
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
- Medical Scientist Training Program, Northwestern University Feinberg School of Medicine, Chicago, IL
| | | | - Vincent L. Butty
- BioMicro Center, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - William C. Hahn
- Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Marc L. Mendillo
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Yu-Shan Lin
- Department of Chemistry, Tufts University, Medford, MA, USA
| | - Matthew D. Shoulders
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
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7
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Cordani M, Garufi A, Benedetti R, Tafani M, Aventaggiato M, D’Orazi G, Cirone M. Recent Advances on Mutant p53: Unveiling Novel Oncogenic Roles, Degradation Pathways, and Therapeutic Interventions. Biomolecules 2024; 14:649. [PMID: 38927053 PMCID: PMC11201733 DOI: 10.3390/biom14060649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 05/24/2024] [Accepted: 05/28/2024] [Indexed: 06/28/2024] Open
Abstract
The p53 protein is the master regulator of cellular integrity, primarily due to its tumor-suppressing functions. Approximately half of all human cancers carry mutations in the TP53 gene, which not only abrogate the tumor-suppressive functions but also confer p53 mutant proteins with oncogenic potential. The latter is achieved through so-called gain-of-function (GOF) mutations that promote cancer progression, metastasis, and therapy resistance by deregulating transcriptional networks, signaling pathways, metabolism, immune surveillance, and cellular compositions of the microenvironment. Despite recent progress in understanding the complexity of mutp53 in neoplastic development, the exact mechanisms of how mutp53 contributes to cancer development and how they escape proteasomal and lysosomal degradation remain only partially understood. In this review, we address recent findings in the field of oncogenic functions of mutp53 specifically regarding, but not limited to, its implications in metabolic pathways, the secretome of cancer cells, the cancer microenvironment, and the regulating scenarios of the aberrant proteasomal degradation. By analyzing proteasomal and lysosomal protein degradation, as well as its connection with autophagy, we propose new therapeutical approaches that aim to destabilize mutp53 proteins and deactivate its oncogenic functions, thereby providing a fundamental basis for further investigation and rational treatment approaches for TP53-mutated cancers.
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Affiliation(s)
- Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain
| | - Alessia Garufi
- Unit of Cellular Networks and Molecular Therapeutic Targets, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;
| | - Rossella Benedetti
- Department of Experimental Medicine, University La Sapienza, 00161 Rome, Italy; (R.B.); (M.T.); (M.A.); (M.C.)
| | - Marco Tafani
- Department of Experimental Medicine, University La Sapienza, 00161 Rome, Italy; (R.B.); (M.T.); (M.A.); (M.C.)
| | - Michele Aventaggiato
- Department of Experimental Medicine, University La Sapienza, 00161 Rome, Italy; (R.B.); (M.T.); (M.A.); (M.C.)
| | - Gabriella D’Orazi
- Unit of Cellular Networks and Molecular Therapeutic Targets, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy;
- Department of Neurosciences, Imaging and Clinical Sciences, University G. D’Annunzio, 00131 Chieti, Italy
| | - Mara Cirone
- Department of Experimental Medicine, University La Sapienza, 00161 Rome, Italy; (R.B.); (M.T.); (M.A.); (M.C.)
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8
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Novikova S, Tolstova T, Kurbatov L, Farafonova T, Tikhonova O, Soloveva N, Rusanov A, Zgoda V. Systems Biology for Drug Target Discovery in Acute Myeloid Leukemia. Int J Mol Sci 2024; 25:4618. [PMID: 38731835 PMCID: PMC11083274 DOI: 10.3390/ijms25094618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 04/18/2024] [Accepted: 04/20/2024] [Indexed: 05/13/2024] Open
Abstract
Combining new therapeutics with all-trans-retinoic acid (ATRA) could improve the efficiency of acute myeloid leukemia (AML) treatment. Modeling the process of ATRA-induced differentiation based on the transcriptomic profile of leukemic cells resulted in the identification of key targets that can be used to increase the therapeutic effect of ATRA. The genome-scale transcriptome analysis revealed the early molecular response to the ATRA treatment of HL-60 cells. In this study, we performed the transcriptomic profiling of HL-60, NB4, and K562 cells exposed to ATRA for 3-72 h. After treatment with ATRA for 3, 12, 24, and 72 h, we found 222, 391, 359, and 1032 differentially expressed genes (DEGs) in HL-60 cells, as well as 641, 1037, 1011, and 1499 DEGs in NB4 cells. We also found 538 and 119 DEGs in K562 cells treated with ATRA for 24 h and 72 h, respectively. Based on experimental transcriptomic data, we performed hierarchical modeling and determined cyclin-dependent kinase 6 (CDK6), tumor necrosis factor alpha (TNF-alpha), and transcriptional repressor CUX1 as the key regulators of the molecular response to the ATRA treatment in HL-60, NB4, and K562 cell lines, respectively. Mapping the data of TMT-based mass-spectrometric profiling on the modeling schemes, we determined CDK6 expression at the proteome level and its down-regulation at the transcriptome and proteome levels in cells treated with ATRA for 72 h. The combination of therapy with a CDK6 inhibitor (palbociclib) and ATRA (tretinoin) could be an alternative approach for the treatment of acute myeloid leukemia (AML).
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MESH Headings
- Humans
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Tretinoin/pharmacology
- Systems Biology/methods
- HL-60 Cells
- Gene Expression Profiling
- K562 Cells
- Drug Discovery/methods
- Transcriptome
- Cell Line, Tumor
- Cyclin-Dependent Kinase 6/metabolism
- Cyclin-Dependent Kinase 6/genetics
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Gene Expression Regulation, Leukemic/drug effects
- Tumor Necrosis Factor-alpha/metabolism
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Affiliation(s)
| | | | | | | | | | | | | | - Victor Zgoda
- Institute of Biomedical Chemistry, Pogodinskaya 10, 119121 Moscow, Russia; (S.N.) (T.T.); (L.K.); (T.F.); (O.T.); (N.S.); (A.R.)
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9
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Zoltsman G, Dang TL, Kuchersky M, Faust O, Silva MS, Ilani T, Wentink AS, Bukau B, Rosenzweig R. A unique chaperoning mechanism in class A JDPs recognizes and stabilizes mutant p53. Mol Cell 2024; 84:1512-1526.e9. [PMID: 38508184 DOI: 10.1016/j.molcel.2024.02.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 12/14/2023] [Accepted: 02/20/2024] [Indexed: 03/22/2024]
Abstract
J-domain proteins (JDPs) constitute a large family of molecular chaperones that bind a broad spectrum of substrates, targeting them to Hsp70, thus determining the specificity of and activating the entire chaperone functional cycle. The malfunction of JDPs is therefore inextricably linked to myriad human disorders. Here, we uncover a unique mechanism by which chaperones recognize misfolded clients, present in human class A JDPs. Through a newly identified β-hairpin site, these chaperones detect changes in protein dynamics at the initial stages of misfolding, prior to exposure of hydrophobic regions or large structural rearrangements. The JDPs then sequester misfolding-prone proteins into large oligomeric assemblies, protecting them from aggregation. Through this mechanism, class A JDPs bind destabilized p53 mutants, preventing clearance of these oncoproteins by Hsp70-mediated degradation, thus promoting cancer progression. Removal of the β-hairpin abrogates this protective activity while minimally affecting other chaperoning functions. This suggests the class A JDP β-hairpin as a highly specific target for cancer therapeutics.
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Affiliation(s)
- Guy Zoltsman
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 761000, Israel
| | - Thi Lieu Dang
- Center for Molecular Biology of Heidelberg University (ZMBH) and German Cancer Research Center (DKFZ), DKFZ-ZMBH-Alliance, Im Neuenheimer Feld 282, Heidelberg 69120, Germany
| | - Miriam Kuchersky
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 761000, Israel
| | - Ofrah Faust
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 761000, Israel
| | - Micael S Silva
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 761000, Israel
| | - Tal Ilani
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 761000, Israel
| | - Anne S Wentink
- Center for Molecular Biology of Heidelberg University (ZMBH) and German Cancer Research Center (DKFZ), DKFZ-ZMBH-Alliance, Im Neuenheimer Feld 282, Heidelberg 69120, Germany; Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333CC Leiden, the Netherlands
| | - Bernd Bukau
- Center for Molecular Biology of Heidelberg University (ZMBH) and German Cancer Research Center (DKFZ), DKFZ-ZMBH-Alliance, Im Neuenheimer Feld 282, Heidelberg 69120, Germany.
| | - Rina Rosenzweig
- Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 761000, Israel.
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10
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Nakamura ET, Park A, Pereira MA, Kikawa D, Tustumi F. Prognosis value of heat-shock proteins in esophageal and esophagogastric cancer: A systematic review and meta-analysis. World J Gastrointest Oncol 2024; 16:1578-1595. [PMID: 38660660 PMCID: PMC11037039 DOI: 10.4251/wjgo.v16.i4.1578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 12/24/2023] [Accepted: 01/23/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Heat shock proteins (HSPs) are molecular chaperones that play an important role in cellular protection against stress events and have been reported to be overexpressed in many cancers. The prognostic significance of HSPs and their regulatory factors, such as heat shock factor 1 (HSF1) and CHIP, are poorly understood. AIM To investigate the relationship between HSP expression and prognosis in esophageal and esophagogastric cancer. METHODS A systematic review was conducted in accordance with PRISMA recommendations (PROSPERO: CRD42022370653), on Embase, PubMed, Cochrane, and LILACS. Cohort, case-control, and cross-sectional studies of patients with esophagus or esophagogastric cancer were included. HSP-positive patients were compared with HSP-negative, and the endpoints analyzed were lymph node metastasis, tumor depth, distant metastasis, and overall survival (OS). HSPs were stratified according to the HSP family, and the summary risk difference (RD) was calculated using a random-effect model. RESULTS The final selection comprised 27 studies, including esophageal squamous cell carcinoma (21), esophagogastric adenocarcinoma (5), and mixed neoplasms (1). The pooled sample size was 3465 patients. HSP40 and 60 were associated with a higher 3-year OS [HSP40: RD = 0.22; 95% confidence interval (CI): 0.09-0.35; HSP60: RD = 0.33; 95%CI: 0.17-0.50], while HSF1 was associated with a poor 3-year OS (RD = -0.22; 95%CI: -0.32 to -0.12). The other HSP families were not associated with long-term survival. HSF1 was associated with a higher probability of lymph node metastasis (RD = -0.16; 95%CI: -0.29 to -0.04). HSP40 was associated with a lower probability of lymph node dissemination (RD = 0.18; 95%CI: 0.03-0.33). The expression of other HSP families was not significantly related to tumor depth and lymph node or distant metastasis. CONCLUSION The expression levels of certain families of HSP, such as HSP40 and 60 and HSF1, are associated with long-term survival and lymph node dissemination in patients with esophageal and esophagogastric cancer.
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Affiliation(s)
- Eric Toshiyuki Nakamura
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
- Department of Scientific Initiation, Universidade Mogi das Cruzes, São Paulo 08780911, Brazil
| | - Amanda Park
- Department of Evidence-Based Medicine, Centro Universitário Lusíada, Centre for Evidence-Based Medicine, Centro Universitário Lusíada (UNILUS), Santos, Brazil
| | - Marina Alessandra Pereira
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
| | - Daniel Kikawa
- Department of Scientific Initiation, Universidade Mogi das Cruzes, São Paulo 08780911, Brazil
| | - Francisco Tustumi
- Department of Gastroenterology, Instituto do Câncer, Hospital das Clínicas da Universidade de São Paulo, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01246000, Brazil
- Department of Surgery, Hospital Israelita Albert Einstein, São Paulo 05652900, Brazil
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Isermann T, Schneider KL, Wegwitz F, De Oliveira T, Conradi LC, Volk V, Feuerhake F, Papke B, Stintzing S, Mundt B, Kühnel F, Moll UM, Schulz-Heddergott R. Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.22.581507. [PMID: 38464125 PMCID: PMC10925225 DOI: 10.1101/2024.02.22.581507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
The stress-associated molecular chaperone system is an actionable target in cancer therapies. It is ubiquitously upregulated in cancer tissues and enables tumorigenicity by stabilizing hundreds of oncoproteins and disturbing the stoichiometry of protein complexes. Most inhibitors target the key component heat-shock protein 90 (HSP90). However, although classical HSP90 inhibitors are highly tumor-selective, they fail in phase 3 clinical oncology trials. These failures are at least partly due to an interference with a negative feedback loop by HSP90 inhibition, known as heat-shock response (HSR): in response to HSP90 inhibition there is compensatory synthesis of stress-inducible chaperones, mediated by the transcription factor heat-shock factor 1 (HSF1). We recently identified that wildtype p53 (p53) actively reduces the HSR by repressing HSF1 via a p21-CDK4/6-MAPK-HSF1 axis. Here we test the hypothesis that in HSP90-based therapies simultaneous p53 activation or direct cell cycle inhibition interrupts the deleterious HSF1-HSR axis and improves the efficiency of HSP90 inhibitors. Indeed, we find that the clinically relevant p53 activator Idasanutlin suppresses the HSF1-HSR activity in HSP90 inhibitor-based therapies. This combination synergistically reduces cell viability and accelerates cell death in p53-proficient colorectal cancer (CRC) cells, murine tumor-derived organoids and patient-derived organoids (PDOs). Mechanistically, upon combination therapy human CRC cells strongly upregulate p53-associated pathways, apoptosis, and inflammatory immune pathways. Likewise, in the chemical AOM/DSS CRC model in mice, dual HSF1-HSP90 inhibition strongly represses tumor growth and remodels immune cell composition, yet displays only minor toxicities in mice and normal mucosa-derived organoids. Importantly, inhibition of the cyclin dependent kinases 4 and 6 (CDK4/6) under HSP90 inhibition phenocopies synergistic repression of the HSR in p53-proficient CRC cells. Even more important, in p53-deficient (mutp53-harboring) CRC cells, an HSP90 inhibition in combination with CDK4/6 inhibitors similarly suppresses the HSF1-HSR system and reduces cancer growth. Likewise, p53-mutated PDOs strongly respond to dual HSF1-HSP90 pathway inhibition and thus, providing a strategy to target CRC independent of the p53 status. In sum, activating p53 (in p53-proficient cancer cells) or inhibiting CDK4/6 (independent of the p53 status) provide new options to improve the clinical outcome of HSP90-based therapies and to enhance colorectal cancer therapy.
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Affiliation(s)
- Tamara Isermann
- Department of Molecular Oncology, University Medical Center Göttingen, Göttingen, Germany
- Charité – Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, Berlin, Germany
- German Cancer Consortium (DKTK); Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Kim Lucia Schneider
- Department of Molecular Oncology, University Medical Center Göttingen, Göttingen, Germany
| | - Florian Wegwitz
- Department of Gynecology and Obstetrics, University Medical Center Göttingen, Göttingen, Germany
| | - Tiago De Oliveira
- Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Germany
| | - Lena-Christin Conradi
- Department of General, Visceral, and Pediatric Surgery, University Medical Center Göttingen, Germany
| | - Valery Volk
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | | | - Björn Papke
- Charité – Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, Berlin, Germany
- German Cancer Consortium (DKTK); Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sebastian Stintzing
- Charité – Universitätsmedizin Berlin, Department of Hematology, Oncology, and Cancer Immunology, Berlin, Germany
| | - Bettina Mundt
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Florian Kühnel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ute M. Moll
- Department of Pathology, Stony Brook University, Stony Brook, NY
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Drastichova Z, Trubacova R, Novotny J. Regulation of phosphosignaling pathways involved in transcription of cell cycle target genes by TRH receptor activation in GH1 cells. Biomed Pharmacother 2023; 168:115830. [PMID: 37931515 DOI: 10.1016/j.biopha.2023.115830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/30/2023] [Accepted: 10/31/2023] [Indexed: 11/08/2023] Open
Abstract
Thyrotropin-releasing hormone (TRH) is known to activate several cellular signaling pathway, but the activation of the TRH receptor (TRH-R) has not been reported to regulate gene transcription. The aim of this study was to identify phosphosignaling pathways and phosphoprotein complexes associated with gene transcription in GH1 pituitary cells treated with TRH or its analog, taltirelin (TAL), using label-free bottom-up mass spectrometry-based proteomics. Our detailed analysis provided insight into the mechanism through which TRH-R activation may regulate the transcription of genes related to the cell cycle and proliferation. It involves control of the signaling pathways for β-catenin/Tcf, Notch/RBPJ, p53/p21/Rbl2/E2F, Myc, and YY1/Rb1/E2F through phosphorylation and dephosphorylation of their key components. In many instances, the phosphorylation patterns of differentially phosphorylated phosphoproteins in TRH- or TAL-treated cells were identical or displayed a similar trend in phosphorylation. However, some phosphoproteins, especially components of the Wnt/β-catenin/Tcf and YY1/Rb1/E2F pathways, exhibited different phosphorylation patterns in TRH- and TAL-treated cells. This supports the notion that TRH and TAL may act, at least in part, as biased agonists. Additionally, the deficiency of β-arrestin2 resulted in a reduced number of alterations in phosphorylation, highlighting the critical role of β-arrestin2 in the signal transduction from TRH-R in the plasma membrane to transcription factors in the nucleus.
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Affiliation(s)
- Zdenka Drastichova
- Department of Physiology, Faculty of Science, Charles University, 128 00 Prague, Czechia
| | - Radka Trubacova
- Department of Physiology, Faculty of Science, Charles University, 128 00 Prague, Czechia; Institute of Physiology, Czech Academy of Sciences, 142 20 Prague, Czechia
| | - Jiri Novotny
- Department of Physiology, Faculty of Science, Charles University, 128 00 Prague, Czechia.
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Fan YC, Meng ZY, Zhang CS, Wei DW, Wei WS, Xie XD, Huang ML, Jiang LH. DNAJ heat shock protein family member C1 can regulate proliferation and migration in hepatocellular carcinoma. PeerJ 2023; 11:e15700. [PMID: 37520264 PMCID: PMC10386825 DOI: 10.7717/peerj.15700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 06/14/2023] [Indexed: 08/01/2023] Open
Abstract
Background DNAJ heat shock protein family (Hsp40) member C1(DNAJC1) is a member of the DNAJ family. Some members of the DNAJ gene family had oncogenic properties in many cancers. However, the role of DNAJC1 in hepatocellular carcinoma (HCC) was unclear. Methods In this study, expression and prognostic value of DNAJC1 in HCC were analyzed by bioinformatics. Quantitative real-time PCR and Western blotting were used to verify DNAJC1 expression in liver cancer cell lines. Furthermore, immunohistochemical (IHC) was used to detect DNAJC1 expression in liver cancer tissues. Subsequently, the effect of DNAJC1 on the proliferation, migration, invasion and apoptosis of HCC cells was detected by knocking down DNAJC1. Finally, gene set enrichment analysis (GSEA) was used to investigate the potential mechanism of DNAJC1 and was verified by Western blotting. Results DNAJC1 was highly expressed in HCC and was significantly associated with the prognosis of patients with HCC. Importantly, the proliferation, migration and invasion of Huh7 and MHCC97H cells were inhibited by the knockdown of DNAJC1 and the knockdown of DNAJC1 promoted Huh7 and MHCC97H cell apoptosis. Furthermore, compared to the negative control group, DNAJC1 knockdown in Huh7 and MHCC97H cells promoted the expression of p21, p53, p-p53(Ser20), Bax and E-cadherin proteins, while inhibiting the expression of PARP, MMP9, Vimentin, Snai1, Bcl-2 and N-cadherin proteins. Conclusions DNAJC1 had a predictive value for the prognosis of HCC. Knockdown of DNAJC1 may inhibit HCC cell proliferation, migration and invasion and promote the HCC cell apoptosis through p53 and EMT signaling pathways.
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Affiliation(s)
- Yu-Chun Fan
- Medical College, Guangxi University, Nanning, Guangxi, China
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, China
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Zhejiang, China
| | - Zhi-Yong Meng
- First Clinical Medical College, Guangxi Traditional Chinese Medical University, Nanning, China
| | - Chao-Sheng Zhang
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, China
| | - De-Wei Wei
- School of Stomatology, Youjiang Medical University for Nationalities, Baise, China
| | - Wan-Shuo Wei
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, China
| | - Xian-Dong Xie
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, China
| | - Ming-Lu Huang
- School of Stomatology, Youjiang Medical University for Nationalities, Baise, China
| | - Li-He Jiang
- Medical College, Guangxi University, Nanning, Guangxi, China
- School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, China
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Zhejiang, China
- Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, Shanxi, China
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Salzano A, Fioriniello S, D'Onofrio N, Balestrieri ML, Aiese Cigliano R, Neglia G, Della Ragione F, Campanile G. Transcriptomic profiles of the ruminal wall in Italian Mediterranean dairy buffaloes fed green forage. BMC Genomics 2023; 24:133. [PMID: 36941576 PMCID: PMC10029215 DOI: 10.1186/s12864-023-09215-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 02/28/2023] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND Green feed diet in ruminants exerts a beneficial effect on rumen metabolism and enhances the content of milk nutraceutical quality. At present, a comprehensive analysis focused on the identification of genes, and therefore, biological processes modulated by the green feed in buffalo rumen has never been reported. We performed RNA-sequencing in the rumen of buffaloes fed a total mixed ration (TMR) + the inclusion of 30% of ryegrass green feed (treated) or TMR (control), and identified differentially expressed genes (DEGs) using EdgeR and NOISeq tools. RESULTS We found 155 DEGs using EdgeR (p-values < 0.05) and 61 DEGs using NOISeq (prob ≥0.8), 30 of which are shared. The rt-qPCR validation suggested a higher reliability of EdgeR results as compared with NOISeq data, in our biological context. Gene Ontology analysis of DEGs identified using EdgeR revealed that green feed modulates biological processes relevant for the rumen physiology and, then, health and well-being of buffaloes, such as lipid metabolism, response to the oxidative stress, immune response, and muscle structure and function. Accordingly, we found: (i) up-regulation of HSD17B13, LOC102410803 (or PSAT1) and HYKK, and down-regulation of CDO1, SELENBP1 and PEMT, encoding factors involved in energy, lipid and amino acid metabolism; (ii) enhanced expression of SIM2 and TRIM14, whose products are implicated in the immune response and defense against infections, and reduced expression of LOC112585166 (or SAAL1), ROR2, SMOC2, and S100A11, encoding pro-inflammatory factors; (iii) up-regulation of NUDT18, DNAJA4 and HSF4, whose products counteract stressful conditions, and down-regulation of LOC102396388 (or UGT1A9) and LOC102413340 (or MRP4/ABCC4), encoding detoxifying factors; (iv) increased expression of KCNK10, CACNG4, and ATP2B4, encoding proteins modulating Ca2+ homeostasis, and reduced expression of the cytoskeleton-related MYH11 and DES. CONCLUSION Although statistically unpowered, this study suggests that green feed modulates the expression of genes involved in biological processes relevant for rumen functionality and physiology, and thus, for welfare and quality production in Italian Mediterranean dairy buffaloes. These findings, that need to be further confirmed through the validation of additional DEGs, allow to speculate a role of green feed in the production of nutraceutical molecules, whose levels might be enhanced also in milk.
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Affiliation(s)
- Angela Salzano
- Department of Veterinary Medicine and Animal Production, Federico II University, Naples, Italy
| | | | - Nunzia D'Onofrio
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | | | | | - Gianluca Neglia
- Department of Veterinary Medicine and Animal Production, Federico II University, Naples, Italy
| | - Floriana Della Ragione
- Institute of Genetics and Biophysics 'A. Buzzati-Traverso', CNR, Naples, Italy.
- IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Isernia, Italy.
| | - Giuseppe Campanile
- Department of Veterinary Medicine and Animal Production, Federico II University, Naples, Italy
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Xu Y, Tao T, Li S, Tan S, Liu H, Zhu X. Prognostic model and immunotherapy prediction based on molecular chaperone-related lncRNAs in lung adenocarcinoma. Front Genet 2022; 13:975905. [PMID: 36313456 PMCID: PMC9606628 DOI: 10.3389/fgene.2022.975905] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 09/21/2022] [Indexed: 11/17/2022] Open
Abstract
Introduction: Molecular chaperones and long non-coding RNAs (lncRNAs) have been confirmed to be closely related to the occurrence and development of tumors, especially lung cancer. Our study aimed to construct a kind of molecular chaperone-related long non-coding RNAs (MCRLncs) marker to accurately predict the prognosis of lung adenocarcinoma (LUAD) patients and find new immunotherapy targets. Methods: In this study, we acquired molecular chaperone genes from two databases, Genecards and molecular signatures database (MsigDB). And then, we downloaded transcriptome data, clinical data, and mutation information of LUAD patients through the Cancer Genome Atlas (TCGA). MCRLncs were determined by Spearman correlation analysis. We used univariate, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis to construct risk models. Kaplan-meier (KM) analysis was used to understand the difference in survival between high and low-risk groups. Nomogram, calibration curve, concordance index (C-index) curve, and receiver operating characteristic (ROC) curve were used to evaluate the accuracy of the risk model prediction. In addition, we used gene ontology (GO) enrichment analysis and kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses to explore the potential biological functions of MCRLncs. Immune microenvironmental landscapes were constructed by using single-sample gene set enrichment analysis (ssGSEA), tumor immune dysfunction and exclusion (TIDE) algorithm, “pRRophetic” R package, and “IMvigor210” dataset. The stem cell index based on mRNAsi expression was used to further evaluate the patient’s prognosis. Results: Sixteen MCRLncs were identified as independent prognostic indicators in patients with LUAD. Patients in the high-risk group had significantly worse overall survival (OS). ROC curve suggested that the prognostic features of MCRLncs had a good predictive ability for OS. Immune system activation was more pronounced in the high-risk group. Prognostic features of the high-risk group were strongly associated with exclusion and cancer-associated fibroblasts (CAF). According to this prognostic model, a total of 15 potential chemotherapeutic agents were screened for the treatment of LUAD. Immunotherapy analysis showed that the selected chemotherapeutic drugs had potential application value. Stem cell index mRNAsi correlates with prognosis in patients with LUAD. Conclusion: Our study established a kind of novel MCRLncs marker that can effectively predict OS in LUAD patients and provided a new model for the application of immunotherapy in clinical practice.
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Affiliation(s)
- Yue Xu
- Marine Medical Research Institute, Guangdong Medical University, Zhanjiang, China
| | - Tao Tao
- Department of Gastroscope, Zibo Central Hospital, Zibo, China
| | - Shi Li
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, China
| | - Shuzhen Tan
- Department of Dermatology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Haiyan Liu
- Department of Cardiovascular Medicine, Nanchong Central Hospital, The Affiliated Nanchong Central Hospital of North Sichuan Medical College, Nanchong, China
- *Correspondence: Haiyan Liu, ; Xiao Zhu,
| | - Xiao Zhu
- Marine Medical Research Institute, Guangdong Medical University, Zhanjiang, China
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, China
- Laboratory of Molecular Diagnosis, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- *Correspondence: Haiyan Liu, ; Xiao Zhu,
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Kang YJ, Yang WG, Chae WS, Kim DW, Kim SG, Rotaru H. Administration of 4‑hexylresorcinol increases p53‑mediated transcriptional activity in oral cancer cells with the p53 mutation. Oncol Rep 2022; 48:160. [PMID: 35856441 PMCID: PMC9350967 DOI: 10.3892/or.2022.8375] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 06/30/2022] [Indexed: 11/30/2022] Open
Abstract
The p53 mutation is inherent in over 50% of human cancers. In head and neck squamous cell carcinoma, the p53 mutation is associated with a poor prognosis. 4-Hexylresorcinol (4HR) is a pharmacologic chaperone. The present study aimed to investigate the effect of 4HR on p53 transcriptional activity in oral carcinoma cells with p53 mutations. To identify conformational changes induced by 4HR administration, peptides including the DNA-binding domain from mutant and wild-type p53 were synthesized, and Fourier transform infrared spectroscopy was performed. To determine the effect of 4HR on p53 mutant carcinoma cells, western blot analysis, p53 transcriptional activity analysis, MTT assay and apoptosis immunocytochemistry were performed. The YD-15 cell line has a mutation in the DNA binding domain of p53 (Glu258Ala). When p53 Ala-258 was coupled by 4HR, the p53 Ala-258 structure lost its original conformation and approached a conformation similar to that of p53 Glu-258. In the cell experiments, 4HR administration to p53 mutant cells increased p53 transcriptional activity and the expression levels of apoptosis-associated proteins such as B-cell lymphoma 2 (BCL2), BCL2-associated X (BAX) and BCL2-associated agonist of cell death (BAD). Accordingly, 4HR administration on YD-15 cells decreased cell viability and increased apoptosis. In conclusion, 4HR is a potential substance for use in the recovery of loss-of-function in mutant p53 as a pharmacologic chaperone.
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Affiliation(s)
- Yei-Jin Kang
- Department of Oral and Maxillofacial Surgery, Gangneung‑Wonju National University, Gangneung, Gangwon-do 25457, Republic of Korea
| | - Won-Geun Yang
- Daegu Center, Korea Basic Science Institute, Daegu 41566, Republic of Korea
| | - Weon-Sik Chae
- Daegu Center, Korea Basic Science Institute, Daegu 41566, Republic of Korea
| | - Dae-Won Kim
- Department of Oral Biochemistry, College of Dentistry, Gangneung‑Wonju National University, Gangneung, Gangwon-do 25457, Republic of Korea
| | - Seong-Gon Kim
- Department of Oral and Maxillofacial Surgery, Gangneung‑Wonju National University, Gangneung, Gangwon-do 25457, Republic of Korea
| | - Horatiu Rotaru
- Department of Cranio‑Maxillofacial Surgery, 'Iuliu Hatieganu' University of Medicine and Pharmacy, Cluj‑Napoca 400000, Romania
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Abstract
Background: Mutation of p53 is a frequent event, and mutant p53 exhibits low levels of acetylation and phosphorylation. This study aimed to investigate the effect of the histone deacetylase (HDAC) inhibitor, 4-hexylresorcinol (4HR), on the acetylation and phosphorylation of mutant p53 carcinoma cells and its therapeutic effects in a xenograft model. Methods: To determine the effect of 4HR on the acetylation and phosphorylation of p53, western blot analysis was performed using YD-9 and YD-15 cells. p53 siRNA was used to examine whether 4HR acts in a p53-dependent or independent manner. This was evaluated using a xenograft model. Results: In in vitro experiments when the concentration of 4HR was increased, the expression levels of HDAC4, acetylated p53 (Ac-p53), and phosphorylated p53 (p-p53) increased. Transfection with TP53 siRNA successfully suppressed p53 protein and TP53 mRNA expression. When 4HR was administered to a xenograft model, the tumour expansion rate was suppressed compared with the control, and the mice exhibited a higher survival rate. Conclusions: Our findings reveal that 4HR is a potential agent that restores loss of function in mutant p53 cancer cells via acetylation and phosphorylation of p53 as well as inhibition of HDAC4.
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