• AKT inhibitor
• Advanced solid tumor
• First-in-human
• Pharmacodynamics
• Pharmacokinetics

• Humans
• Male
• Female
• Neoplasms/drug therapy
• Neoplasms/pathology
• Middle Aged
• Aged
• Proto-Oncogene Proteins c-akt/antagonists & inhibitors
• Adult
• Dose-Response Relationship, Drug
• Maximum Tolerated Dose
• Protein Kinase Inhibitors/pharmacokinetics
• Protein Kinase Inhibitors/administration & dosage
• Protein Kinase Inhibitors/adverse effects
• Protein Kinase Inhibitors/therapeutic use
• Antineoplastic Agents/pharmacokinetics
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/adverse effects
• Antineoplastic Agents/therapeutic use
• Aged, 80 and over
• Allosteric Regulation/drug effects
• Pyrazoles
• Thiophenes

• Taiho Pharmaceutical

• chemoresistance
• extracellular vesicles
• invasion
• microme
• ovarian cancer

• Humans
• Tumor Suppressor Protein p53/metabolism
• Tumor Suppressor Protein p53/genetics
• Female
• Drug Resistance, Neoplasm
• Phosphorylation
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• Ovarian Neoplasms/drug therapy
• Extracellular Vesicles/metabolism
• Carboplatin/pharmacology
• Carboplatin/therapeutic use
• Cell Line, Tumor
• Bifidobacterium longum/metabolism
• Apoptosis/drug effects
• Cell Proliferation/drug effects
• Cell Movement/drug effects

• 2021S00164 Wenling Science and Technology Project
• 21ywb125 Taizhou Social Development Science and Technology Plan Project

• Nanodrug delivery
• Ovarian cancer
• Platinum resistance
• circRNA NUP50
• p53

• Animals
• Humans
• Female
• Cisplatin/pharmacology
• Cisplatin/therapeutic use
• MicroRNAs/metabolism
• RNA, Circular/genetics
• RNA, Circular/metabolism
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• DNA Helicases/genetics
• DNA Helicases/metabolism
• Cell Line, Tumor
• Poly-ADP-Ribose Binding Proteins/genetics
• Poly-ADP-Ribose Binding Proteins/metabolism
• RNA Helicases/genetics
• RNA Helicases/metabolism
• RNA Helicases/therapeutic use
• RNA Recognition Motif Proteins/genetics
• RNA Recognition Motif Proteins/metabolism
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/pathology
• Ubiquitination
• Cell Proliferation
• Drug Resistance, Neoplasm
• Ubiquitin-Conjugating Enzymes

• 82172652 National Natural Science Foundation of China
• 2016YFC1303700 National Key Research and Development Program of China

• ATM
• DNA-PK
• cisplatin sensitivity
• homologous recombination
• integrin signaling
• mutant p53
• non-homologous end joining
• triple negative breast cancer

• R21 CA178753 NCI NIH HHS
• R01 CA223164 NCI NIH HHS
• P20 GM121327 NIGMS NIH HHS
• P30 CA177558 NCI NIH HHS
• R01 CA131075 NCI NIH HHS
• National Institutes of Health

The extracellular matrix (ECM) plays an important role in the progression of cancer. Collagen is the most abundant component in ECM, and is involved in the biological formation of cancer. Although type XI collagen is a minor fibrillar collagen, collagen XI alpha 1 chain (COL11A1) expression has been found to be upregulated in a variety of human cancers including colorectal, esophagus, glioma, gastric, head and neck, lung, ovarian, pancreatic, salivary gland, and renal cancers. High levels of COL11A1 usually predict poor prognosis, owing to its association with angiogenesis, invasion, and drug resistance in cancer. However, little is known about the specific mechanism through which COL11A1 regulates tumor progression. Here, we have organized and summarized recent developments regarding the interactions between COL11A1 and intracellular signaling pathways and selected therapeutic agents targeting COL11A1, as these indicate its potential as a target for treatment of cancers, especially epithelial ovarian cancer.

• cancer associated fibroblast activation
• cancer progression
• chemoresistance
• collagen type XI alpha 1
• epithelial ovarian cancer

Cisplatin (cis-diamminedichloroplatinum (II)) is the oldest known chemotherapeutic agent. Since the identification of its anti-tumour activity, it earned a remarkable place as a treatment of choice for several cancer types. It remains effective against testicular, bladder, lung, head and neck, ovarian, and other cancers. Cisplatin treatment triggers different cellular responses. However, it exerts its cytotoxic effects by generating inter-strand and intra-strand crosslinks in DNA. Tumour cells often develop tolerance mechanisms by effectively repairing cisplatin-induced DNA lesions or tolerate the damage by adopting translesion DNA synthesis. Cisplatin-associated nephrotoxicity is also a huge challenge for effective therapy. Several preclinical and clinical studies attempted to understand the major limitations associated with cisplatin therapy, and so far, there is no definitive solution. As such, a more comprehensive molecular and genetic profiling of patients is needed to identify those individuals that can benefit from platinum therapy. Additionally, the treatment regimen can be improved by combining cisplatin with certain molecular targeted therapies to achieve a balance between tumour toxicity and tolerance mechanisms. In this review, we discuss the importance of various biological processes that contribute to the resistance of cisplatin and its derivatives. We aim to highlight the processes that can be modulated to suppress cisplatin resistance and provide an insight into the role of uptake transporters in enhancing drug efficacy.

• Antineoplastic Agents/metabolism
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Cisplatin/pharmacology
• Cisplatin/therapeutic use
• DNA/therapeutic use
• DNA Repair
• Drug Resistance, Neoplasm
• Humans
• Neoplasms/drug therapy

Mitochondrial dynamics (e.g. fission/fusion) play an important role in controlling chemoresistance in representative gynecologic malignancies, ovarian and cervical cancer. Processing the long form of Optic atrophy (L-Opa)1 is a distinctive character of mitochondrial fragmentation, associated with chemosensitivity. Here, we examined the role of prohibitin (Phb)1 in increasing L-Opa1 processing via the regulating mitochondrial protease, Oma1 and its direct interaction with p-p53 (ser15) and pro-apoptotic Bcl-2 antagonist/killer (Bak) 1 in the signaling axis and if this phenomenon is associated with prognosis of patients.

We compared Cisplatin (CDDP)-induced response of mitochondrial dynamics, molecular interaction among p-p53 (ser15)-Phb1-Bak, and chemoresponsiveness in paired chemosensitive and chemoresistant gynecologic cancer cells (ovarian and cervical cancer cell lines) using western blot, immunoprecipitation, sea horse, and immunofluorescence. Translational strategy with proximity ligation assessment in phb1-p-p53 (ser15) in human ovarian tumor sections further confirmed in vitro finding, associated with clinical outcome.

We report that: (1) Knock-down of Phb1 prevents Cisplatin (cis-diamine-dichloroplatinum; CDDP) -induced changes in mitochondrial fragmentation and Oma1 mediated cleavage, and Opa1 processing; (2) In response to CDDP, Phb1 facilitates the p-p53 (ser15)-Phb1-Bak interaction in mitochondria in chemosensitive gynecologic cancer cells but not in chemoresistant cells; (3) Akt overexpression results in suppressed p-p53(Ser15)-Phb1 interaction and dysregulated mitochondrial dynamics, and (4) Consistent with in vitro findings, proximity ligation assessment (PLA) in human ovarian tumor sections demonstrated that p-p53(ser15)-Phb1-Bak interaction in mitochondria is associated with better chemoresponsiveness and clinical outcome of patients. Determining the molecular mechanisms by which Phb1 facilitates mitochondrial fragmentation and interacts with p53 may advance the current understanding of chemoresistance and pathogenesis of gynecologic cancer.

Determining the key molecular mechanisms by which Phb1 facilitates the formation of p-p53 (ser15)-Bak-Phb1 and its involvement in the regulation of mitochondrial dynamics and apoptosis may ultimately contribute to the current understanding of molecular and cellular basis of chemoresistance in this gynecologic cancer.

The online version contains supplementary material available at 10.1186/s13048-022-00999-x.

• Bak
• CDDP
• Chemoresistance
• Mitochondrial fragmentation
• Phb1
• p53

Cisplatin resistance is the main cause of poor clinical prognosis in patients with gastric cancer (GC). Yet, the exact mechanism underlying cisplatin resistance remains unclear. Recent studies have suggested that exocrine miRNAs found in the tumor microenvironment participate in tumor metastasis and drug resistance.

Exosomes isolated from BGC823 and BGC823/DDP culture medium were characterized by transmission electron microscopy and differential ultracentrifugation, and miRNA expression profiles of BGC823 and BGC823/DDP cells derived exosomes were analyzed using miRNA microarray. In vivo and in vitro assays were used to identify roles of exosomal miR‐769‐5p and clarify the mechanism of exosomal miR‐769‐5p regulated the crosstalk between sensitive and resistant GC cells.

In this study, we found that cisplatin‐resistant GC cells communicated with the tumor microenvironment by secreting microvesicles. MiR‐769‐5p was upregulated in GC tissues and enriched in the serum exosomes of cisplatin‐resistant patients. The biologically active miR‐769‐5p could be integrated into exosomes and delivered to sensitive cells, spreading cisplatin resistance. Underlying cellular and molecular mechanism was miR‐769‐5p targeting CASP9, thus inhibiting the downstream caspase pathway and promoting the degradation of the apoptosis‐related protein p53 through the ubiquitin‐proteasome pathway. Targeting miR‐769‐5p with its antagonist to treat cisplatin‐resistant GC cells can restore the cisplatin response, confirming that exosomal miR‐769‐5p can act as a key regulator of cisplatin resistance in GC.

These findings indicate that exosome‐transmitted miR‐769‐5p confers cisplatin resistance and progression in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53. These findings reveal exosomal miR‐769‐5p derived from drug‐resistant cells can be used as a potential therapeutic predictor of anti‐tumor chemotherapy to enhance the effect of anti‐cancer chemotherapy, which provides a new treatment option for GC.

• CASP9
• cisplatin resistance
• gastric cancer
• miR-769-5p
• p53

• Caspase 9/genetics
• Caspase 9/metabolism
• Cisplatin/pharmacology
• Drug Resistance, Neoplasm/genetics
• Exosomes/genetics
• Humans
• MicroRNAs/genetics
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Tumor Microenvironment
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Ubiquitination/genetics

• National Natural Science Foundation of China

Ovarian cancer is the eighth most commonly diagnosed cancer among women worldwide. Even with the development of novel drugs, nearly one-half of the patients with ovarian cancer die within five years of diagnosis. These situations indicate the need for novel therapeutic agents for ovarian cancer. Increasing evidence has shown that hypoxia-inducible factor-1α(HIF-1α) plays an important role in promoting malignant cell chemoresistance, tumour metastasis, angiogenesis, immunosuppression and intercellular interactions. The unique microenvironment, crosstalk and/or interaction between cells and other characteristics of ovarian cancer can influence therapeutic efficiency or promote the disease progression. Inhibition of the expression or activity of HIF-1α can directly or indirectly enhance the therapeutic responsiveness of tumour cells. Therefore, it is reasonable to consider HIF-1α as a potential therapeutic target for ovarian cancer. In this paper, we summarize the latest research on the role of HIF-1α and molecules which can inhibit HIF-1α expression directly or indirectly in ovarian cancer, and drug clinical trials about the HIF-1α inhibitors in ovarian cancer or other solid malignant tumours.

• hypoxia-inducible factors
• molecular target
• ovarian cancer
• targeted therapy
• tumour microenvironment

• Yes-associated protein
• chemoresistance
• epithelial-mesenchymal transition
• ovarian cancer
• substrate stiffness

Hexokinase II (HKII) is a key glycolysis enzyme associated with tumorigenesis, but its molecular mechanism and pathophysiological role in chemoresistant ovarian cancer remain elusive. In this study, we delineate the novel mechanism showing that activated phosphorylated-p53 (P-p53 Ser15) is required for the regulation of HKII intracellular trafficking and metabolic regulation in chemosensitive ovarian cancer, but not in chemoresistant ovarian cancer harboring p53 mutation. We have observed that increased nuclear HKII-P-p53 (Ser15) interaction is likely associated with chemosensitivity and better survival outcomes in epithelial ovarian cell lines, human primary epithelial ovarian cancer cells, and tumor sections. Nuclear HKII-P-p53 (Ser15) interaction may function as a promising prognostic biomarker, enabling prediction of patients with poor prognosis for deciding better clinical strategies.

In epithelial ovarian cancer (EOC), carboplatin/cisplatin-induced chemoresistance is a major hurdle to successful treatment. Aerobic glycolysis is a common characteristic of cancer. However, the role of glycolytic metabolism in chemoresistance and its impact on clinical outcomes in EOC are not clear. Here, we show a functional interaction between the key glycolytic enzyme hexokinase II (HKII) and activated P-p53 (Ser15) in the regulation of bioenergetics and chemosensitivity. Using translational approaches with proximity ligation assessment in cancer cells and human EOC tumor sections, we showed that nuclear HKII-P-p53 (Ser15) interaction is increased after chemotherapy, and functions as a determinant of chemoresponsiveness as a prognostic biomarker. We also demonstrated that p53 is required for the intracellular nuclear HKII trafficking in the control of glycolysis in EOC, associated with chemosensitivity. Mechanistically, cisplatin-induced P-p53 (Ser15) recruits HKII and apoptosis-inducing factor (AIF) in chemosensitive EOC cells, enabling their translocation from the mitochondria to the nucleus, eliciting AIF-induced apoptosis. Conversely, in p53-defective chemoresistant EOC cells, HKII and AIF are strongly bound in the mitochondria and, therefore, apoptosis is suppressed. Collectively, our findings implicate nuclear HKII-P-p53(Ser15) interaction in chemosensitivity and could provide an effective clinical strategy as a promising biomarker during platinum-based therapy.

• P-p53 (Ser15)
• cancer metabolism
• chemoresistance
• epithelial ovarian cancer
• hexokinase II

The multidrug resistance of EAC is one of the major obstacles to chemotherapeutic efficiency. Our study aims to explore the molecular mechanism of AKR1C3 as a novel therapeutic target to overcome chemotherapy resistance for EAC patients. We demonstrate that AKR1C3 renders chemotherapy resistance through controlling cellular ROS levels via AKT signaling in EAC cells. Modulation of intracellular GSH levels by AKR1C3 could scavenge the intracellular ROS, thus regulating apoptosis. Targeting AKR1C3 may represent a novel strategy to sensitize EAC cells to conventional chemotherapy treatment and benefit the overall survival of patients diagnosed with EAC.

Esophageal adenocarcinoma (EAC) is one of the most lethal malignancies, and limits promising treatments. AKR1C3 represents a therapeutic target to combat the resistance in many cancers. However, the molecular mechanism of AKR1C3 in the chemotherapy resistance of EAC is still unclear. We found that the mRNA level of AKR1C3 was higher in EAC tumor tissues, and that high AKR1C3 expression might be associated with poor overall survival of EAC patients. AKR1C3 overexpression decreased cell death induced by chemotherapeutics, while knockdown of AKR1C3 attenuated the effect. Furthermore, we found AKR1C3 was inversely correlated with ROS production. Antioxidant NAC rescued chemotherapy-induced apoptosis in AKR1C3 knockdown cells, while the GSH biosynthesis inhibitor BSO reversed a protective effect of AKR1C3 against chemotherapy. AKT phosphorylation was regulated by AKR1C3 and might be responsible for eliminating over-produced ROS in EAC cells. Intracellular GSH levels were modulated by AKR1C3 and the inhibition of AKT could reduce GSH level in EAC cells. Here, we reported for the first time that AKR1C3 renders chemotherapy resistance through controlling ROS levels via AKT signaling in EAC cells. Targeting AKR1C3 may represent a novel strategy to sensitize EAC cells to conventional chemotherapy.

• AKR1C3
• AKT signaling
• ROS regulation
• chemotherapy resistance
• esophageal adenocarcinoma
• prognosis

Cervical cancer is the fourth leading cause of cancer-related death among women worldwide. The chemotherapeutical agent cisplatin, a small platinum-based compound, is considered as the standard therapy for locally advanced cervical cancer or recurrent cancers, sometimes in combination with radiotherapy or other drugs. However, drug resistance and radio-resistance phenomena could reduce the life expectancy of cervical cancer patients. Resistance mechanisms are complex and often involve multiple cellular pathways in which microRNAs (miRNAs) play a fundamental role. miRNAs are a class of endogenous non-coding small RNAs responsible for post-transcriptional gene regulation. Convincing evidence demonstrates that several deregulated miRNAs are important regulators in the onset of drug and radioresistance in cervical cancer, thus underlying their potential applications in a clinical setting. In this review, we summarized the mechanisms by which miRNAs affect both cisplatin and radioresistance in cervical cancer. We also described the regulatory loops between miRNAs and lncRNAs promoting drug resistance. Besides, we reported evidence for the role of miRNAs in sensitizing cancer cells to cisplatin-based chemotherapy, and provided some suggestions for the development of new combined therapies for cervical cancer.

• cervical cancer
• cisplatin
• cisplatin resistance
• drug resistance
• microRNA
• radiotherapy

• Apoptosis
• Autophagy
• Cell Line, Tumor
• Cisplatin/pharmacology
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress/drug effects
• Female
• Humans
• Kaempferols/pharmacology
• Ovarian Neoplasms/pathology
• Proto-Oncogene Proteins c-akt/antagonists & inhibitors
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction

Conventional chemotherapeutic regimens are unable to prevent metastasis of non-small cell lung carcinoma (NSCLC) thereby leaving cancer incurable. Cancer stem cells (CSCs) are considered to be the origin of this therapeutic limitation. In the present study we report that the migration potential of NSCLCs is linked to its CSC content. While cisplatin alone fails to inhibit the migration of CSC-enriched NSCLC spheroids, in a combination with non-steroidal anti inflammatory drug (NSAID) aspirin retards the same. A search for the underlying mechanism revealed that aspirin pre-treatment abrogates p300 binding both at TATA-box and initiator (INR) regions of mTOR promoter of CSCs, thereby impeding RNA polymerase II binding at those sites and repressing mTOR gene transcription. As a consequence of mTOR down-regulation, Akt is deactivated via dephosphorylation at Ser⁴⁷³ residue thereby activating Gsk3β that in turn causes destabilization of Snail and β-catenin, thus reverting epithelial to mesenchymal transition (EMT). However, alone aspirin fails to hinder migration since it does not inhibit the Integrin/Fak pathway, which is highly activated in NSCLC stem cells. On the other hand, in aspirin pre-treated CSCs, cisplatin stalls migration by hindering the integrin pathway. These results signify the efficacy of aspirin in sensitizing NSCLC stem cells towards the anti-migration effect of cisplatin. Cumulatively, our findings raise the possibility that aspirin might emerge as a promising drug in combinatorial therapy with the existing chemotherapeutic agents that fail to impede migration of NSCLC stem cells otherwise. This may consequently lead to the advancement of remedial outcome for the metastatic NSCLCs.

The mTOR/S6K1 signaling pathway is often activated in cervical cancer, and thus considered a molecular target for cervical cancer therapies. Inhibiting mTOR is cytotoxic to cervical cancer cells and creates a synergistic anti-tumor effect with conventional chemotherapy agents. In this study, we identified a novel S6K1 inhibitor, rosmarinic acid methyl ester (RAME) for the use of therapeutic agent against cervical cancer.

Combined structure- and ligand-based virtual screening was employed to identify novel S6K1 inhibitors among the in house natural product library. In vitro kinase assay and immunoblot assay was used to examine the effects of RAME on S6K1 signaling pathway. Lipidation of LC3 and mRNA levels of ATG genes were observed to investigate RAME-mediated autophagy. PARP cleavage, mRNA levels of apoptotic genes, and cell survival was measured to examine RAME-mediated apoptosis.

RAME was identified as a novel S6K1 inhibitor through the virtual screening. RAME, not rosmarinic acid, effectively reduced mTOR-mediated S6K1 activation and the kinase activity of S6K1 by blocking the interaction between S6K1 and mTOR. Treatment of cervical cancer cells with RAME promoted autophagy and apoptosis, decreasing cell survival rate. Furthermore, we observed that combination treatment with RAME and cisplatin greatly enhanced the anti-tumor effect in cisplatin-resistant cervical cancer cells, which was likely due to mTOR/S6K1 inhibition-mediated autophagy and apoptosis.

Our findings suggest that inhibition of S6K1 by RAME can induce autophagy and apoptosis in cervical cancer cells, and provide a potential option for cervical cancer treatment, particularly when combined with cisplatin.

The online version of this article (10.1186/s12885-019-5997-2) contains supplementary material, which is available to authorized users.

• Apoptosis
• Autophagy
• Cervical cancer
• Cisplatin resistance
• Rosmarinic acid methyl ester
• S6K1

Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths primarily due to chemoresistance. Somatic mutation of TP53 (36%) and epidermal growth factor receptor (EGFR; > 30%) are major contributors to cisplatin (CDDP) resistance. Substantial evidence suggests the elevated levels of reactive oxygen species (ROS) is a key determinant in cancer. The elevated ROS can affect the cellular responses to chemotherapeutic treatments. Although the role of EGFR in PI3K/Akt signaling cascade in NSCLC is extensively studied, the molecular link between EGFR and p53 and the role of ROS in pathogenesis of NSCLC are limitedly addressed. In this study, we investigated the role of p53 in regulation of ROS production and EGFR signaling, and the chemosensitivity of NSCLC.

In multiple NSCLC cell lines with varied p53 and EGFR status, we compared and examined the protein contents involved in EGFR-Akt-P53 signaling loop (EGFR, P-EGFR, Akt, P-Akt, p53, P-p53) by Western blot. Apoptosis was determined based on nuclear morphological assessment using Hoechst 33258 staining. Cellular ROS levels were measured by dichlorofluorescin diacetate (DCFDA) staining followed by flow cytometry analysis.

We have demonstrated for the first time that activation of p53 sensitizes chemoresistant NSCLC cells to CDDP by down-regulating EGFR signaling pathway and promoting intracellular ROS production. Likewise, blocking EGFR/PI3K/AKT signaling with PI3K inhibitor elicited a similar response. Our findings suggest that CDDP-induced apoptosis in chemosensitive NSCLC cells involves p53 activation, leading to suppressed EGFR signaling and ROS production. In contrast, in chemoresistant NSCLC, activated Akt promotes EGFR signaling by the positive feedback loop and suppresses CDDP-induced ROS production and apoptosis.

Collectively, our study reveals that the interaction of the p53 and Akt feedback loops determine the fate of NSCLC cells and their CDDP sensitivity.

The online version of this article (10.1186/s12935-019-0910-2) contains supplementary material, which is available to authorized users.

• Chemoresistance
• Cis-diaminedichloroplatinum (Cisplatin) (CDDP)
• Epidermal growth factor (EGFR)
• Non-small cell lung cancer (NSCLC)
• p53 reactive oxygen species (ROS)

This study investigated the effect of acylated synthetic ghrelin (AG) on the survival and proliferation of human chemosensitive ovarian cancer cells (A2780) and explored some mechanisms of action with a focus on the p53 apoptotic pathway and PI3K/Akt and NF-κB survival pathways. Human A2780 ovarian cancer cells were cultured with or without AG treatment in the presence or absence of cisplatin. In some cases, cisplatin+AG-treated cells were pre-incubated either with [D-Lys3]-GHRP-6, a ghrelin receptor antagonist, or with LY294002, a PI3K inhibitor. mRNA of ghrelin receptors(GHS-R1a and GHS-R1b), as well as, protein levels of GHS-R1a, were expressed abundantly in A2780 cells. AG treatment did not affect the mRNA and protein levels of GHS-R1a and GHS-R1b in both control and Cis-treated cells. However, while AG treatment had no effect on control cell viability, it significantly increased cell viability and proliferation and inhibited cell death in Cis-treated cells. In both control and Cis-treated cells, AG treatment significantly increased PI3K/Akt/mTOR signaling and enhanced the nuclear accumulation of NF-κB. Concomitantly, in both control and Cis-treated cells, AG significantly lowered the protein levels of p53, p-p53 (Ser16), PUMA, cytochrome C, and cleaved caspase-3. Interestingly, pre-incubating the cells with either [D-Lys3]-GHRP-6 or LY294002 completely abolished the above-mentioned effect of AG in both control and Cis-treated cells. In conclusion, the findings of this study show that AG promotes cell survival of the OC cells and renders them resistat to Cis therapy, an effect that is mediated by the activation of PI3K/Akt/mTOR and activation of NF-κB, and requires GHS-R1a.

• Chemo-therapy
• advanced ovarian cancer
• biomarkers
• proteomics

Ovarian cancer is the most lethal of all gynecologic malignancies and the eighth leading cause of cancer-related deaths among women worldwide. The main reasons for this poor prognosis are late diagnosis; when the disease is already in an advanced stage, and the frequent development of resistance to current chemotherapeutic regimens. Growing evidence demonstrates that apart from its role in ovarian cancer progression, epithelial-to-mesenchymal transition (EMT) can promote chemotherapy resistance. In this review, we will highlight the contribution of EMT to the distinct steps of ovarian cancer progression. In addition, we will review the different types of ovarian cancer resistance to therapy with particular attention to EMT-mediated mechanisms such as cell fate transitions, enhancement of cancer cell survival, and upregulation of genes related to drug resistance. Preclinical studies of anti-EMT therapies have yielded promising results. However, before anti-EMT therapies can be effectively implemented in clinical trials, more research is needed to elucidate the mechanisms leading to EMT-induced therapy resistance.

• cancer stem cell (CSC)
• epithelial-to-mesenchymal transition (EMT)
• mesenchymal-to-epithelial transition (MET)
• ovarian cancer
• peritoneal metastasis
• therapy resistance

• DDP
• RalBP1
• bioinformatics analysis
• proliferation and apoptosis

• CREBZF
• Cisplatin resistance
• HDAC4
• HIF-1α
• Ras
• p53

• CTR1
• EOC
• Fut8
• cDDP-resistance
• core fucosylation

As a component of p53-dependent lncRNA (long non-coding RNA), PANDAR (the promoter of CDKN1A antisense DNA damage activated RNA) participates in the epigenetic regulation in human cancer. However, the involvement of PANDAR in cancer chemoresistance is unknown. In this study, we report that PANDAR serves as a negative regulator of cisplatin sensitivity in human ovarian cancer via PANDAR-SRFS2-p53 feedback regulation in nuclear. Our data showed that among the drugs commonly used in ovarian cancer therapy, cisplatin induces higher levels of PANDAR compared with doxorubicin and paclitaxel. We also proved that PANDAR exhibited higher expression in cisplatin-resistant ovarian cancer tissues and cells, compared with cisplatin-sensitive ones, and this expression pattern depends on wild-type p53 (wt-p53), not mutant-p53 (mt-p53). In vitro and in vivo, PANDAR overexpression improved cell survival rate and tumor growth in response to cisplatin, while depletion of PANDAR leads to a reduced tumor growth. Further investigation revealed that PANDAR-reduced cisplatin sensitivity was likely or partly due to the PANDAR-binding protein SFRS2 (arginine/serine-rich 2), a splicing factor with the ability to negative regulate p53 and its phosphorylation at Serine 15 (Ser15). This feedback regulation of PANDAR–SFRS2–p53 leads to a reduced transactivation of p53-related pro-apoptotic genes, such as PUMA (p53-upregulated modulator of apoptosis). In addition, in platinum-treated patients with relapsed ovarian cancer, resistant period was positively correlated with the expression of PANDAR and SFRS2, and inversely associated with expression of p53-Ser15 and PUMA in these clinical tissues. Last but not least, the role of PANDAR in chemoresistance was confirmed in patients with ovarian cancer. These findings reveal a novel regulatory maneuver of cancer cells in response to chemostress, and might shed light on overcoming cisplatin resistance in ovarian cancer.

• cisplatin resistance
• gastric cancer
• integrated stress response (ISR)
• salubrinal
• xCT

• Activating Transcription Factor 4/metabolism
• Amino Acid Transport System y+/genetics
• Antineoplastic Agents/pharmacology
• Cell Line, Tumor
• Cinnamates/pharmacology
• Cisplatin/pharmacology
• Drug Resistance, Neoplasm
• Eukaryotic Initiation Factor-2/antagonists & inhibitors
• Eukaryotic Initiation Factor-2/metabolism
• Gene Expression Regulation, Neoplastic/drug effects
• Glutathione/metabolism
• Humans
• Oxidative Stress/drug effects
• Reactive Oxygen Species/metabolism
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Thiourea/analogs & derivatives
• Thiourea/pharmacology
• Up-Regulation/drug effects

• CY10605, CY10707 Cheng Hsin General Hospital
• Aim for the Top University Plan Ministry of Education
• MOST 106-2320-B-010-032 and MOST 107-2320-B-010-044 Ministry of Science and Technology, Taiwan
• SPROUT Project- Center For Intelligent Drug Systems and Smart Bio-devices (IDS2B) National Chiao Tung University, from the Ministry of Education, Taiwan.
• V105A-018 and V106A-020 Taipei Veterans General Hospital, Taipei, Taiwan

Resistance to cisplatin (CDDP) is a major cause of cancer treatment failure, including human breast cancer. The tumor suppressor protein p53 is a key factor in the induction of cell cycle arrest, DNA repair, and apoptosis in response to cellular stimuli. This protein is phosphorylated in serine 15 and serine 20 during DNA damage repair or in serine 46 to induce apoptosis. Resveratrol (Resv) is a natural compound representing a promising chemosensitizer for cancer treatment that has been shown to sensitize tumor cells through upregulation and phosphorylation of p53 and inhibition of RAD51. We developed a CDDP-resistant MCF-7 cell line variant (MCF-7_R) to investigate the effect of Resv in vitro in combination with CDDP over the role of p53 in overcoming CDDP resistance in MCF-7_R cells. We have shown that Resv induces sensitivity to CDDP in MCF-7 and MCF-7_R cells and that the downregulation of p53 protein expression and inhibition of p53 protein activity enhances resistance to CDDP in both cell lines. On the other hand, we found that Resv induces serine 20 (S20) phosphorylation in chemoresistant cells to activate p53 target genes such as PUMA and BAX, restoring apoptosis. It also changed the ratio between BCL-2 and BAX, where BCL-2 protein expression was decreased and at the same time BAX protein was increased. Interestingly, Resv attenuates CDDP-induced p53 phosphorylation in serine 15 (S15) and serine 46 (S46) probably through dephosphorylation and deactivation of ATM. It also activates different kinases, such as CK1, CHK2, and AMPK to induce phosphorylation of p53 in S20, suggesting a novel mechanism of p53 activation and chemosensitization to CDDP.

• breast cancer
• cisplatin
• p53
• phosphorylation
• resistance
• resveratrol

• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Cell Survival/drug effects
• Checkpoint Kinase 2/genetics
• Checkpoint Kinase 2/metabolism
• Cisplatin/pharmacology
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Humans
• MCF-7 Cells
• Phosphorylation
• Proto-Oncogene Proteins c-bcl-2/genetics
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Resveratrol/pharmacology
• Serine/chemistry
• Tumor Suppressor Protein p53/chemistry
• Tumor Suppressor Protein p53/genetics
• bcl-2-Associated X Protein/genetics
• bcl-2-Associated X Protein/metabolism

• CD4 T cell
• epitope
• head and neck squamous cell carcinoma
• immunotherapy
• p53
• phosphorylation
• post-translational modification

• carboplatin
• chemoresistance
• epithelial ovarian cancer
• p38 MAPK
• primary EOC cells
• surviving

• Antineoplastic Agents/pharmacology
• Carboplatin/pharmacology
• Carcinoma, Ovarian Epithelial
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Drug Resistance, Neoplasm/drug effects
• Enzyme Inhibitors/pharmacology
• Female
• Humans
• Imidazoles/pharmacology
• Neoplasms, Glandular and Epithelial/drug therapy
• Neoplasms, Glandular and Epithelial/metabolism
• Neoplasms, Glandular and Epithelial/pathology
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• Phosphorylation/drug effects
• Pyridines/pharmacology
• Tumor Cells, Cultured
• p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
• p38 Mitogen-Activated Protein Kinases/metabolism

• chemoresistance
• hexokinase 2
• ovarian cancer
• p53
• tumor metabolism

• ATM/Chk2
• MAPK
• PI3K/Akt
• ovarian cancer
• propadiene compound

The aims of this study were to investigate the functions of GAS5 as a tumor suppressor in cervical cancer and explore the mechanism.

The expression of GAS5 and microRNA 21 (miR-21) was detected in primary cervical cancer tissue specimens, as well as in cervical cancer cell lines. We identified the interaction of GAS5 and miR-21 by quantitative polymerase chain reaction, Western blot, and dual-luciferase reporter assay. We also studied the functions of GAS5 in proliferation, apoptosis, migration, and invasion in cervical cancer cells in vitro and vivo. Finally, the impact of GAS5 on cisplatin resistance and its mechanism in cervical cancer cells was also identified.

The expression of GAS5 and miR-21 was detected in primary cervical cancer tissue specimens, as well as in cervical cancer cell lines. GAS5, which is a tumor suppressor playing roles in inhibiting the malignancy of cervical cancer cells, including proliferation in vivo and vitro, migration, and invasion, has a low expression in cervical cancer tissue and cervical cancer cell lines, whereas miR-21 expression is high. GAS5 significantly decreased the expression of miR-21, and there is a reciprocal repression of gene expression between GAS5 and miR-21. Besides, most importantly, we found that high expression of GAS5 and low expression of miR-21 can enhance the sensitivity of SiHa/cDDP cancer cells to cisplatin. A further experiment for identifying the mechanism of cisplatin resistance by GAS5 showed that GAS5 can not only regulate phosphatase and tensin homolog through miR-21 but also influence the phosphorylation of Akt.

Our results indicate that GAS5 is a direct target of miR-21 and can predict the clinical staging of cervical cancer. Most importantly, GAS5 can also influence cisplatin resistance in cervical cancer via regulating the phosphorylation of Akt. All of these suggest that GAS5 may be a novel therapeutic target for treating cervical cancer.

• Ovarian cancer cells
• Ovarian cell lines
• Serine 15
• Serine 20
• p53 phosphorylation

• Adenocarcinoma/metabolism
• Adenocarcinoma/pathology
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Cell Line, Tumor
• Cell Survival/drug effects
• Colonic Neoplasms/metabolism
• Colonic Neoplasms/pathology
• Female
• Humans
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/pathology
• Phosphorylation/drug effects
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Serine/metabolism
• Tumor Suppressor Protein p53/metabolism
• bcl-2-Associated X Protein/metabolism

Cisplatin (CDDP) and its derivatives are first line anti-cancer drugs for ovarian cancer (OVCA). However, chemoresistance due to high incidence of p53 mutations leads to poor clinical prognosis. Saikosaponin-d (Ssd), a saponin from a herbal plant extract, has been shown to induce cell death and sensitize chemoresistant cells to chemotherapeutic agents. Here, we demonstrated that Ssd sensitized chemoresistant OVCA cells with either p53-wt, -mutant and -null to CDDP. The action of Ssd appears to be through induction of mitochondrial fragmentation and G2/M arrest. Ssd is mediated via calcium signaling, up-regulation of the mitochondrial fission proteins Dynamin-related protein 1 (Drp1) and optic atrophy 1 (Opa1), and loss in mitochondrial membrane potential (MMP). Moreover, in the presence of CDDP, Ssd also down-regulates protein phosphatase magnesium-dependent 1 D (PPM1D) and increases the phosphorylation of checkpoint protein kinases (Chk) 1, cell division cycle 25c (Cdc25c) and Cyclin dependent kinase 1 (Cdk1). Our findings suggest that Ssd could sensitize OVCA to CDDP independent of the p53 status through multiple signaling pathways. They support the notion that Ssd may be a novel adjuvant for the treatment of chemoresistant OVCA.

• G2/M arrest
• Ssd
• chemoresistance
• mitochondrial dynamics
• ovarian cancer

• Acute Lung Injury
• Apoptosis
• Baicalein
• Mitogen-Activated Protein Kinases
• Myocardial Ischemia and Reperfusion
• Prosurvival Kinases

• PI3K
• chemoresistance
• estrogen
• gynecological cancers
• targeted therapies

• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Apoptosis Regulatory Proteins/genetics
• Clinical Trials as Topic
• Drug Resistance, Neoplasm/drug effects
• Endometrial Neoplasms/drug therapy
• Endometrial Neoplasms/genetics
• Estrogens/pharmacology
• Estrogens/therapeutic use
• Female
• Gene Regulatory Networks/drug effects
• Humans
• Molecular Targeted Therapy/methods
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/genetics
• Treatment Outcome

The dysregulated microRNAs contribute to cisplatin resistance in ovarian cancer cells.

• AKT
• Bcl-2
• cisplatin
• drug resistance
• epithelial ovarian cancer

• Abietane diterpenoid
• Apoptosis
• Cisplatin
• Gastric cancer cells
• Rosmarinus officinalis
• Sageone

• Antineoplastic Agents, Phytogenic/chemistry
• Antineoplastic Agents, Phytogenic/isolation & purification
• Antineoplastic Agents, Phytogenic/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Apoptosis/drug effects
• Cell Cycle/drug effects
• Cell Line, Tumor
• Cisplatin/administration & dosage
• Cisplatin/pharmacology
• Diterpenes/isolation & purification
• Diterpenes/pharmacology
• Drug Screening Assays, Antitumor
• Hexanes/chemistry
• Humans
• Membrane Potential, Mitochondrial/drug effects
• Molecular Structure
• Rosmarinus/chemistry
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/pathology