mTORC1/2 inhibitor and curcumin induce apoptosis through lysosomal membrane permeabilization-mediated autophagy

• Published in: Oncogene Vol. 37; no. 38; pp. 5205 - 5220
• Main Authors: Seo, Seung Un, Woo, Seon Min, Lee, Hyun-Shik, Kim, Sang Hyun, Min, Kyoung-jin, Kwon, Taeg Kyu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2018; Nature Publishing Group
• Subjects: 13/109; 13/2; 13/31; 13/89; 14/19; 38/109; 38/89; 631/67/1059/602; 631/67/1059/99; AKT protein; Apoptosis; Autophagy; BAX protein; Bcl-2 protein; Biochemistry; Calcium (reticular); Cancer; Cancer treatment; Carcinoma; Care and treatment; Cell Biology; Cell culture; Cell death; Curcumin; Development and progression; Endoplasmic reticulum; Genetic aspects; Health aspects; Human Genetics; Internal Medicine; Kidney cancer; Lysosomes; Mcl-1 protein; Medicine; Medicine & Public Health; Oncology; Phagocytosis; Phosphotransferases; Renal cell carcinoma; TOR protein; Tumors; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0345-6

mTOR is an important regulator of cell growth and forms two complexes, mTORC1/2. In cancer, mTOR signaling is highly activated, and the regulation of this signaling, as an anti-cancer strategy, has been emphasized. However, PP242 (inhibitor of mTORC1 and mTORC2) alone did not induce human renal carcinoma cell death. In this study, we found that PP242 alone did not alter cell viability, but combined curcumin and PP242 treatment induced cell death. Combined PP242 and curcumin treatment induced Bax activation and decreased expression of Mcl-1 and Bcl-2. Furthermore, co-treatment with PP242 and curcumin-induced the downregulation of the Rictor (an mTORC2 complex protein) and Akt protein levels, and ectopic overexpression of Rictor or Akt inhibited PP242 plus curcumin induced cell death. Downregulation of Rictor increased cytosolic Ca 2+ release from endoplasmic reticulum, which led to lysosomal damage in PP242 plus curcumin-treated cells. Furthermore, damaged lysosomes induced autophagy. Autophagy inhibitors markedly inhibited cell death. Finally, combined curcumin and PP242 treatment reduced tumor growth and induced cell death in xenograft models. Altogether, our results reveal that combined PP242 and curcumin treatment could induce autophagy-mediated cell death by reducing the expression of Rictor and Akt in renal carcinoma cells.