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

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 (ALDH1(high)) cells from the human prostate cancer 22Rv1 cell line using an ALDEFLUOR assay and established several ALDH1(high) and ALDH1(low) clones. ALDH1(high) 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 ALDH1(high) clones showed lower phosphorylated AKT (Ser473) (pAKT) levels than the ALDH1(low) 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 ALDH1(high) and ALDH1(low) cells; the fold increase rate of pAKT was higher in ALDH1(high) cells than in ALDH1(low) cells. Insulin induced resistance to radiation and chemotherapy in ALDH1(high) 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. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

The ALDH1-high prostate cancer stem-like cells (CSCs) exhibit heterogeneity in tumorigenicity and resistance to radiation and chemotherapy, along with lower levels of phosphorylated AKT. Insulin can activate AKT signaling in these cells, leading to resistance to radiation and chemotherapy. These findings suggest a potential mechanism for treatment resistance in prostate cancer.