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.
Highlights
MTOR has been known as a regulator of cell growth, proliferation, metastasis, lipogenesis, and transcription. mTOR is involved in two distinct multi-protein complexes, mTORC1/2. mTORC1 contains mTOR, Raptor, GβL, and Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.DEPTOR and phosphorylates S6K and 4EBP1
Since mTORC1/2 signaling plays a pivotal role in cell survival and inhibitors of mTORC1/2 are considered anticancer therapeutic agents [21], we elucidated the effects of mTORC1/2 inhibitor on cell death
Since damaged lysosomes are removed by autophagy and autophagy promotes or inhibits cell death, depending on cancer initiation or maintenance, respectively [38,39,40], we investigated the role of autophagy on PP242 plus curcumininduced apoptosis
Summary
MTOR has been known as a regulator of cell growth, proliferation, metastasis, lipogenesis, and transcription. MTORC2 contains mTOR, GβL, Rictor, Sin, PRR5/ PRR5L, and DEPTOR and regulates Akt and PKC phosphorylation and actin cytoskeleton formation [1]. Rapamycin analogs only inhibit mTORC1, and long-term treatment with the rapamycin analog induces PI3K and Akt activation [4]. Since mTORC1 inhibits PI3K activation via the inhibitory phosphorylation of IRS-1, the chronic inhibition of mTORC1 impedes the negative feedback loop [4]. PP242 and KU63794-induced ERK activation [5, 6], and PP242 transiently inhibits mTOR signaling in some cancer cells [6]. Identifying chemical reagents to improve the effect of mTORC1/2 inhibitors may enhance efficiency for cancer therapy
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