Curcumin Targets Both Apoptosis and Necroptosis in Acidity‐Tolerant Prostate Carcinoma Cells
Yoon‐Jin Lee, Kwan-Sik Park, Sang-Han Lee
Abstract
OBJECTIVE: , is known to have anticancer potential and is still under investigation. In this study, we investigated the cytotoxic mechanism(s) of curcumin against acidity-tolerant prostate cancer PC-3AcT cells in lactic acid-containing medium. METHODS: Using 2D-monolyer and 3D spheroid culture models, MTT assay, annexin V-PE binding assay, flow cytometric analysis, measurement of ATP content, and Western blot analysis were used for this study. RESULTS: peak, annexin V-PE-positive cells, and ROS levels; loss of mitochondrial membrane potential; reduction of cellular ATP content; DNA damage; and concurrent induction of apoptosis and necroptosis. A series of changes induced by curcumin were effectively reversed by reducing ROS levels or replenishing ATP. Pretreatment with apoptosis inhibitor Q-VD-Oph-1 or necroptosis inhibitor necrostatin-1 restored cell viability inhibited by curcumin. Treatment of 3D spheroids with curcumin decreased cell viability, accompanied by an increase in mediators of apoptosis and necroptosis, including cleaved caspase-3 and cleaved PARP, phospho (p)-RIP3, and p-MLKL proteins. CONCLUSION: This study shows that curcumin simultaneously induces apoptosis and necroptosis by oxidative mitochondrial dysfunction and subsequent ATP depletion, providing a mechanistic basis for understanding the novel role of curcumin for prostate carcinoma cells.