High aldehyde dehydrogenase 1 activity is related to radiation resistance due to activation of AKT signaling after insulin stimulation in prostate cancer.

Abstract

The association between type 2 diabetes mellitus and prostate cancer is still under investigation, and the relationship between hyperinsulinemia and prostate cancer stem-like cells (CSCs) is elusive. Here, we investigated the function of insulin/AKT signaling in prostate CSCs. We isolated prostate CSCs as aldehyde dehydrogenase 1-high (ALDH1high) cells from the human prostate cancer 22Rv1 cell line using an ALDEFLUOR assay and established several ALDH1high and ALDH1low clones. ALDH1high clones showed high ALDH1 expression which is a putative CSC marker; however, they showed heterogeneity regarding tumorigenicity and resistance to radiation and chemotherapy. Interestingly, all ALDH1high clones showed lower phosphorylated AKT (Ser473) (pAKT) levels than the ALDH1low clones. PI3K/AKT signaling is a key cell survival pathway and we analyzed radiation resistance under AKT signaling activation by insulin. Insulin increased pAKT levels in ALDH1high and ALDH1low cells; the fold increase rate of pAKT was higher in ALDH1high cells than in ALDH1low cells. Insulin induced resistance to radiation and chemotherapy in ALDH1high cells, and the increased levels of pAKT induced by insulin were significantly related to radiation resistance. These results suggest that ALDH1 suppresses baseline pAKT levels, but AKT can be activated by insulin, leading to treatment resistance.

• Authors: Takahito Wakamiya, Yoshihiko Hirohashi, Aiko Murai, Junko Yanagawa, Yuka Mizue, Terufumi Kubo, Shinichi Hashimoto, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Sachiyo Nishida, Yasuo Kohjimoto, Isao Hara, Toshihiko Torigoe
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 590 Pg. 117-124 (01 29 2022) ISSN: 1090-2104 [Electronic] United States
• PMID: 34974299 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Insulin
• Aldehyde Dehydrogenase
• Proto-Oncogene Proteins c-akt

Topics

• Aldehyde Dehydrogenase (metabolism)
• Animals
• Carcinogenesis (drug effects, pathology)
• Cell Line, Tumor
• Enzyme Activation (drug effects)
• Humans
• Insulin (pharmacology)
• Male
• Mice
• Phosphorylation (drug effects)
• Prostatic Neoplasms (enzymology, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Radiation Tolerance
• Signal Transduction