Basic Study
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World J Gastroenterol. Jul 21, 2022; 28(27): 3422-3434
Published online Jul 21, 2022. doi: 10.3748/wjg.v28.i27.3422
Accumulation of poly (adenosine diphosphate-ribose) by sustained supply of calcium inducing mitochondrial stress in pancreatic cancer cells
Keun-Yeong Jeong, Jae Jun Sim, Minhee Park, Hwan Mook Kim
Keun-Yeong Jeong, Jae Jun Sim, Minhee Park, Hwan Mook Kim, Research and Development, Metimedi Pharmaceuticals, Incheon 22006, South Korea
Author contributions: Jeong KY conceived the project and wrote the paper; Jeong KY and Sim JJ designed the experiments; Jeong KY, Sim JJ, and Park MH performed the experiments; Jeong KY, Sim JJ, and Kim HM analyzed the data; and all authors discussed the results and revised the manuscript.
Institutional animal care and use committee statement: Animal care and experimental procedures were authorized by the Institutional Animal Care and Use Committee at Gachon University (IACUC-LCDI-2019-0102, 16 July 2019).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Keun-Yeong Jeong, PhD, Executive Vice President, Research Assistant Professor, Research and Development, Metimedi Pharmaceuticals, 263 Central-ro, Incheon 22006, South Korea. alvirus@naver.com
Received: January 11, 2022
Peer-review started: January 11, 2022
First decision: March 8, 2022
Revised: March 15, 2022
Accepted: June 26, 2022
Article in press: June 26, 2022
Published online: July 21, 2022
ARTICLE HIGHLIGHTS
Research background

The excessive accumulation of poly adenosine diphosphate(ADP)-ribose (PAR) induces energy deprivation and apoptosis-inducing factor (AIF) release from mitochondria resulting in the caspase-independent death of cancer cells, and an increase in PAR is closely related to an increase in reactive oxygen species (ROS).

Research motivation

Increasing ROS can be induced in cancer cells by calcium influx. Therefore, it would be possible to expect the anticancer effect targeting pancreatic cancer through calcium-dependent PAR accumulation.

Research objectives

This study focused on the accumulation of PAR to induce energy deprivation and AIF release by sustained calcium supply to investigate its potential anticancer effect on pancreatic cancer.

Research methods

Two pancreatic cancer cell lines, AsPC-1 and CFPAC-1 were used for the study. Calcium influx and mitochondrial ROS were observed by fluorescence staining. Changes in enzyme levels, as well as PAR accumulation and energy metabolism, were measured using assay kits. AIF-dependent cell death was investigated followed by confirming in vivo anticancer effects by sustained calcium administration.

Research results

Mitochondrial ROS levels were elevated with increasing calcium influx into pancreatic cancer cells. Then, excess PAR accumulation, decreased PAR glycohydrolase and ADP-ribosyl hydrolase 3 levels, and energy crisis were observed. In vitro and in vivo antitumor effects were confirmed to accompany elevated AIF levels.

Research conclusions

Accumulation of PAR was induced by an increase in ROS following sustained calcium supply, which in turn led to the death of pancreatic cancer cells by energy deprivation and AIF expression. Calcium-mediated accumulation of PAR would be a potential strategy for the treatment of pancreatic cancer.

Research perspectives

Although this study visualized the potential anticancer effects of excessive PAR accumulation by sustained calcium supply on pancreatic cancer, elucidating a clear mode of action remains a challenge, and it should be accompanied by further studies to assess its potential for clinical application.