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

Oncogene
Seung Un SeoTaeg Kyu Kwon

Abstract

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 Ca2+ 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 induc...Continue Reading

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Nov 20, 2019·Medicinal Research Reviews·Tuhina KhanGiuseppe Campiani
Apr 21, 2020·Phytotherapy Research : PTR·Mahsa SalehiHamed Mirzaei
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Methods Mentioned

BETA
flow cytometry
fluorescence microscopy
light microscopy
xenograft
ubiquitination
transfection

Software Mentioned

SPSS ( Statistical Package for the Social Sciences

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