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

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 induce autophagy-mediated cell death by reducing the expression of Rictor and Akt in renal carcinoma cells.

Restoration of Autophagic Flux Rescues Oxidative Damage and Mitochondrial Dysfunction to Protect against Intervertebral Disc Degeneration

“…CUR is a polyphenol that has been confirmed to exert multiple pharmacological effects in both in vitro and in vivo models [50,51]. Intriguingly, CUR has been reported to either promote or inhibit autophagy activity in various cells [52][53][54]. In this study, we found that CUR induced autophagy and enhanced autophagic flux in human NP cells, and we further studied the potential molecular mechanisms by which CUR promotes autophagy.…”

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…Curcumin is shown to induce anti-cancer activities through the disruption of mitochondrial membrane potential and blockade at G2/M phase of the cell cycle in human epidermoid carcinoma A-431 cells [47]. In addition, mammalian target of rapamycin (mTOR) plays a vital role in curcumininduced autophagy and apoptosis [30,[48][49][50]. Curcumin induces apoptosis and autophagy through the inhibition of phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway in human NSCLC A549 cells [30], while it induces autophagy by reducing Akt phosphorylation and mTOR in human melanoma A375 and C8161 cells [49].…”

Curcumin-Mediated Apoptotic Cell Death in Papillary Thyroid Cancer and Cancer Stem-Like Cells through Targeting of the JAK/STAT3 Signaling Pathway

“…Curcumin (diferuloylmethane) is one of the most studied phytochemicals found in plants Curcuma longa (Linn) and has been shown to possess strong antioxidant, anti-inflammatory, and anticancer potential over a range of human cancers [15,16]. In various cancers, curcumin has been shown to inhibit growth and proliferation of cancer cells by targeting various survival pathways, including JAK/STAT3, PI3-kinase/AKT, Transforming growth factor beta (TGF-β), Epidermal Growth Factor Receptor (EFGR), and NF-кB [17][18][19][20][21]. In addition, there is attenuation of the transcriptional expression of regulatory proteins associated with programmed cell death or apoptosis.…”