Repurposing antidepressant sertraline as a pharmacological drug to target prostate cancer stem cells: dual activation of apoptosis and autophagy signaling by deregulating redox balance

Abstract

Cancer stem cells play a major role in tumor initiation, progression, and tumor relapse of prostate cancer (PCa). Recent studies suggest that Translationally Controlled Tumor Protein (TCTP) is a critical survival factor of stem cells including cancer stem cells. Here, we aimed to determine whether the TCTP inhibitor sertraline (STL) could target prostate cancer stem cells (PCSC). In colony formation, spheroidogenesis, angiogenesis, and wound healing assays STL showed a robust inhibition of tumorigenic (colony growth), angiogenic (endothelial tube formation) and metastatic (wound healing and migration) potential of PCSC. Interestingly, antioxidants such as N-acetyl cysteine (NAC), Glutathione (GSH) and catalase effectively blocked the cytotoxicity effect of STL on PCSC implicating oxidative stress as the underlying anti-PCSC targeting mechanism. Cell cycle analysis showed a robust G₀ arrest in PCSC exposed to STL. Notably, STL induced both apoptosis and autophagy by activating free radical generation, hydrogen peroxide formation (H₂O₂), lipid peroxidation (LPO) and depleted the levels of glutathione (GSH). Moreover, surface marker expression analysis using confocal revealed that STL significantly down regulates the expression levels of aldehyde dehydrogenase 1 (ALDH1) and cluster of differentiation 44 (CD44) stem cell markers. Furthermore, in western blot analysis, STL treatment applied in a dose-dependent manner, caused a marked decrease in TCTP, phospho TCTP, anti-apoptotic markers survivin and cellular inhibitor of apoptosis protein 1 (cIAP1) expression as well as a significant increase in cleaved caspase3 and cleaved Poly [ADP-ribose] polymerase 1 (PARP-1) expression. Of note, STL also significantly down regulated the stem cell markers (ALDH1 and CD44) and epithelial to mesenchymal transition (EMT) markers such as transcription factor 8 (TCF8) and lymphoid enhancer-binding factor-1 (LEF1) expression levels. Concurrently, STL increased the levels of autophagy markers such as light chain (LC3), Beclin1 and autophagy-related gene (ATG5). Taken together, our study suggests that STL could be an effective therapeutic agent in eliminating prostate cancer stem cells.

Keywords: Sertraline; TCTP; angiogenesis; antidepressant; apoptosis; autophagy; oxidative stress; prostate cancer; prostate cancer stem cells.