Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells

Abstract

Previous studies have demonstrated that the chronic administration of valproic acid (VPA) suppresses angiogenesis in vivo; however, the mechanisms implicated in VPA-induced autophagy remain unclear. The current study aimed to assess VPA-induced autophagy in three prostate cancer cell lines (PC3, DU145 and LNCaP), in addition to analyzing the Akt/mammalian target of rapamycin (mTOR) signal pathway. Prostate cancer cell lines were cultured with various doses of VPA. Cell cycle was analyzed using flow cytometry, and autophagy markers [1A/1B-light chain 3 (LC3)-II and Beclin-1] were examined using transmission electron microscopy, fluorescent microscopy and western blotting. Activation of the Akt/mTOR signal pathway was also assessed by western blotting. The results demonstrated that VPA induced autophagosomes and suppressed the Akt/mTOR signal pathway. This was confirmed by detection of increased LC3-II and Beclin-1 in VPA-treated cells compared with untreated controls. Phosphorylated forms of Akt (PC3, P=0.048; DU145, P=0.045; LNCaP, P=0.039) and mTOR (PC3, P=0.012; DU145, P=0.41; LNCaP, P=0.35) were significantly reduced following VPA treatment. These results suggest that VPA may function as a histone deacetylase inhibitor, suppressing the growth of prostate cancer cells by modulating autophagy pathways, including inhibition of the Akt/mTOR pathway. Further experiments are required to determine the significance of all involved pathways regarding VPA-induced growth inhibition.

Valproic acid attenuates renal fibrosis through the induction of autophagy

“…A recent study has also reported that VPA induces autophagy by suppression of the mTOR pathway [24]. In this study, VPA improved renal fibrosis along with increased markers of autophagy, whereas inhibition of autophagy worsened renal fibrosis.…”

Evaluation of cell death pathways initiated by antitumor drugs melatonin and valproic acid in bladder cancer cells

“…According to reports in the literature, autophagy can be enhanced [41,42] or reduced [43,44] by melatonin treatment, depending on the cell line. However, as far as we know, majority of the literature indicates that VPA induces autophagy [45,46].…”

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

“…A review of the functional or molecular targeting effects of VPA in acute myeloid leukaemia (AML) cells as well as the relevant clinical trials suggested that clinical studies should investigate whether VPA, or any other drug, should be the preferred HDAC inhibitor in AML . More recent evidence indicating that VPA has anticancer activity has come from studies in cell lines from various cancers such as prostate, cervical, glioblastoma, pancreas, thyroid, breast and bladder . This distinct anticancer property of VPA is also believed to explain, at least partially, the mechanisms underpinning its teratogenic effects …”