Carnosic acid induces autophagic cell death through inhibition of the Akt/mTOR pathway in human hepatoma cells

Abstract

The therapeutic goal of cancer treatment is now geared towards triggering tumour-selective cell death with autophagic cell death being required for the chemotherapy of apoptosis-resistant cancer. In this study, Carnosic acid (CA), a polyphenolic diterpene isolated from Rosemary (Rosemarinus officinalis), significantly induced autophagic cell death in HepG2 cells. Ca treatment caused the formation of autophagic vacuoles produced an increasing ratio of LC3-II to LC3-I in a time- and dose-dependent manner but had no effect on the levels of autophagy-related protein ATG6 and ATG13 expression. Autophagy inhibitors, 3-methyladenine (3-MA), chloroquine and bafilomycin A1, or ATG genes silencing in HepG2 cells significantly inhibited CA-induced autophagic cell death. The CA treatment decreased the levels of phosphorylated Akt and mTOR without any effects on PI3K or PTEN. Most importantly, overexpression of Akt and knockdown of PTEN attenuated autophagy induction in CA-treated cells. Taken together, our results indicated that CA induced autophagic cell death through inhibition of the Akt/mTOR pathway in human hepatoma cells. These findings suggest that CA has a great potential for the treatment of hepatoma via autophagic induction.

Diterpenes from rosemary (Rosmarinus officinalis): Defining their potential for anti-cancer activity

“…The autophagic effect was accompanied by decrease in levels of pAkt and mTOR proteins without any change in phosphoinositide 3-kinase (PI3K) and PTEN protein levels [36].…”

Spices for Prevention and Treatment of Cancers

“…Additionally, carnosol induced apoptosis by affecting the redox status and decreasing glutathione in the adult T-cell leukemia/lymphoma cells (lymphatic) [225]. In addition, carnosic acid significantly induced autophagic cell death in HepG2 cells, which was associated with inhibition of the Akt/mTOR pathway [226]. …”

Nano-liquid Chromatography-orbitrap MS-based Quantitative Proteomics Reveals Differences Between the Mechanisms of Action of Carnosic Acid and Carnosol in Colon Cancer Cells

“…Recent works have reported the involvement of autophagy cell death in the antiproliferative activity of CS and CA in different cancer cell lines (17,25). In this regard, CA-induced autophagic cell death has been closely linked to negative regulation of the Akt/ mTOR pathway in human hepatoma cells (25). Furthermore, blockage of Akt signaling by PTEN expression seems to be a part of the causative mechanism for the antiproliferative effect of CA in leukemia cells (26).…”

“…In addition, CA has been shown to sensitize human renal carcinoma Caki cells to TRAIL-induced apoptosis through downregulation of c-FLIP and Bcl-2 at the post-translational levels and induction of DR5, Bim and PUMA transcription, events that were attributed to the up-regulation of CHOP and ATF4 typically observed in cells under ER stress (24). Recent works have reported the involvement of autophagy cell death in the antiproliferative activity of CS and CA in different cancer cell lines (17,25). In this regard, CA-induced autophagic cell death has been closely linked to negative regulation of the Akt/ mTOR pathway in human hepatoma cells (25).…”