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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1464647

Dehydroepiandrosterone suppresses human colorectal cancer progression through ER stress-mediated autophagy and apoptosis in a p53-independent manner

Provisionally accepted
Thi-Huong Nguyen Thi-Huong Nguyen 1,2Huey-Jiun Ko Huey-Jiun Ko 3,4Po-Yu Tsai Po-Yu Tsai 3,4Tai-Shan Cheng Tai-Shan Cheng 1Peter Mu-Hsin Chang Peter Mu-Hsin Chang 1,5Hsiao-Sheng Liu Hsiao-Sheng Liu 6,7*Yi-Ren Hong Yi-Ren Hong 3,4*Chi-Ying Huang Chi-Ying Huang 1,4*
  • 1 Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
  • 2 Institute of Biotechnology and Food Technology, Thai Nguyen University of Agriculture and Forestry, Thai Nguyen, Vietnam
  • 3 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
  • 4 Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
  • 5 Department of Oncology, Taipei Veterans General Hospital, Taipei, Taipei County, Taiwan
  • 6 Teaching and Research Center, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
  • 7 Center for Cancer Research, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

The final, formatted version of the article will be published soon.

    Colorectal cancer (CRC) is one of the primary contributors to cancer-related fatalities, with up to 80% of advanced CRC cases exhibiting mutations in the p53 gene.Unfortunately, the development of new compounds targeting mutant p53 is quite limited. The anticancer effects of Dehydroepiandrosterone (DHEA) on various cancers have been reported. However, the suppressive effect of DHEA on CRC cells harboring wild-type or mutant p53 gene remains controversial. This study emphasized revealing the suppressive mechanism and the effect of DHEA on CRC cell tumorigenesis in the presence of wild-type or mutant p53 gene. We demonstrate that DHEA causes CRC cell death and cell cycle arrest in a dose and time-dependent manner. Notably, DHEA exhibits similar inhibitory effects on CRC cells regardless of the p53 gene status.Further study reveals that DHEA induces endoplasmic reticulum (ER) stress and triggers PERK/eIF2/ATF4/CHOP UPR signaling pathway to activate autophagy followed by apoptosis, which was confirmed by suppression of 4-phenylbutyric acid (an ER stress inhibitor) or knockdown either ATF4 or CHOP. DHEA-induced apoptosis was attenuated by silencing ATG5 gene in either p53 +/+ or p53 -/-CRC cells, indicating autophagy regulation of apoptosis. Furthermore, DHEA treatment accompanied by bafilomycin A1 (a blocker of autophagosome degradation) leads to the accumulation of ATF4, CHOP, DR5, and p21 levels in CRC cells, implying that the degradative autophagy machinery regulates these four molecules. Consistently, DHEA demonstrates its inhibitory effect by suppressing CRC tumor formation in vivo.Altogether, we provide compelling evidence that DHEA is a potential therapeutic candidate for CRC patient treatment regardless of the p53 status through ER stress-PERK-autophagy-apoptosis axis.

    Keywords: Dehydroepiandrosterone (DHEA), colorectal cancer (CRC), ER stress induction, Autophagy, apoptosis induction, p53 independence

    Received: 14 Jul 2024; Accepted: 16 Sep 2024.

    Copyright: © 2024 Nguyen, Ko, Tsai, Cheng, Chang, Liu, Hong and Huang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Hsiao-Sheng Liu, Teaching and Research Center, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
    Yi-Ren Hong, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
    Chi-Ying Huang, Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.