Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
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
Abstract
BACKGROUND

The biochemical phenomenon defined as poly adenosine diphosphate (ADP)-ribosylation (PARylation) is essential for the progression of pancreatic cancer. However, the excessive accumulation of poly ADP-ribose (PAR) induces apoptosis-inducing factor (AIF) release from mitochondria and energy deprivation resulting in the caspase-independent death of cancer cells.

AIM

To investigate whether sustained calcium supply could induce an anticancer effect on pancreatic cancer by PAR accumulation.

METHODS

Two pancreatic cancer cell lines, AsPC-1 and CFPAC-1 were used for the study. Calcium influx and mitochondrial reactive oxygen species (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.

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 deprivation were observed. In vitro and in vivo antitumor effects were confirmed to accompany elevated AIF levels.

CONCLUSION

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

Keywords: Pancreatic cancer, Calcium, Reactive oxygen species, Poly adenosine diphosphate-ribose, Poly adenosine diphosphate-ribosylation, Poly adenosine diphosphate-ribose polymerase, Apoptosis-inducing factor, Nicotinamide adenine dinucleotide, Anticancer effect

Core Tip: Accumulation of poly adenosine diphosphate-ribose (PAR) was induced by an increase in reactive oxygen species following sustained calcium supply, which in turn led to the death of pancreatic cancer cells by energy deprivation and apoptosis-inducing factor expression. Although calcium-mediated accumulation of PAR would be a potential strategy for the treatment of pancreatic cancer, the association with the mechanical role of calcium in enabling the inactivation of PAR-degrading enzymes needs to be elucidated.