Autophagy Induction by α-Santalol in Human Prostate Cancer Cells

• Published in: Anticancer research 2021-03, Vol.41 (3), p.1197-1202
• Main Authors: Walters, Cole, Reed, Maverick, Bartholomew, Samantha, Bommareddy, Ajay
• Format: Article
• Language: English
• Subjects: Acridine orange; Adenine; Adenine - analogs & derivatives; Adenine - pharmacology; AKT protein; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Autophagy - physiology; Carbon dioxide; Cell death; Cell Line, Tumor; Cell viability; Humans; Immunoblotting; Immunofluorescence; Kinases; Male; Microtubule-associated protein 1; Microtubule-Associated Proteins - metabolism; Organelles; Phagocytosis; Phagosomes; Phosphatidylinositol 4,5-diphosphate; Phosphorylation; Polycyclic Sesquiterpenes - pharmacology; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein-serine/threonine kinase; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Rapamycin; Regulators; Signal Transduction - physiology; TOR protein; TOR Serine-Threonine Kinases - metabolism; Xenografts; Xenotransplantation
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.14876

Previous studies have shown that the sandalwood oil constituent α-santalol inhibits growth of cultured human prostate cancer cells in vitro and PC-3 prostate cancer xenografts. Along with the studies from our laboratory, it is well established that α-santalol targets the phosphatidylinositol-4,5-bisphosphate 3-kinase-AKT serine/ threonine kinase 1 (AKT) pathway to induce apoptosis but its growth-suppressive effects have not been fully elucidated. The current study was undertaken to investigate the role of autophagy in α-santalol-induced prostate cancer cell death. Cell lines LNCaP and PC-3 were maintained in an atmosphere of 95% air and 5% CO2 at 37°C. Trypan blue dye exclusion assay was employed to assess the effects of α-santalol with/without 3-methyl adenine on the cell viability of prostate cancer cells. Acidic vesicular organelles induced by α-santalol treatment were detected by staining with acridine orange. Immunofluorescence and immunoblotting were performed to analyze expression of proteins involved in the AKT-mammalian target of rapamycin (mTOR) pathway. LNCaP and PC-3 cells upon treatment with α-santalol resulted in characteristic features analogous to autophagic response, including formation of acidic vesicular organelles, recruitment and cleavage of microtubule-associated protein 1 light chain 3 (LC3) to autophagosomes. Alpha-santalol treatment further suppressed phosphorylation of activated AKT and mTOR, which are critical regulators of autophagic response. In addition, pre-treatment of PC-3 cells with specific inhibitor of autophagy (3-methyladenine) and co-treatment with α-santalol attenuated the expression of LC3-II and phospho-AKT, and significantly reduced the cell viability. The present study indicates that α-santalol induces autophagy by targeting the AKT-mTOR pathway in prostate cancer cells, which may serve as a protective mechanism.