Abstract
Apogossypolone (ApoG2), a novel derivative of gossypol, exhibits superior antitumor activity in Bcl-2 transgenic mice, and induces autophagy in several cancer cells. However, the detailed mechanisms are not well known. In the present study, we showed that ApoG2 induced autophagy through Beclin-1- and reactive oxygen species (ROS)-dependent manners in human hepatocellular carcinoma (HCC) cells. Incubating the HCC cell with ApoG2 abrogated the interaction of Beclin-1 and Bcl-2/xL, stimulated ROS generation, increased phosphorylation of ERK and JNK, and HMGB1 translocation from the nucleus to cytoplasm while suppressing mTOR. Moreover, inhibition of the ROS-mediated autophagy by antioxidant N-acetyl-cysteine (NAC) potentiates ApoG2-induced apoptosis and cell killing. Our results show that ApoG2 induced protective autophagy in HCC cells, partly due to ROS generation, suggesting that antioxidant may serve as a potential chemosensitizer to enhance cancer cell death through blocking ApoG2-stimulated autophagy. Our novel insights may facilitate the rational design of clinical trials for Bcl-2-targeted cancer therapy.
Highlights
The anti-apoptotic Bcl-2 family proteins consist of Bcl-2, Bcl-xL, Mcl-1, A1 and Bcl-W, which are generally integrated within the outer mitochondrial membrane.[5]
Significant conversion of Light chain 3 (LC3)-I to LC3-II was detected in HepG2 and Hep3B cells treated for 24 h with 10 mM ApoG2 (Figure 1a, rapamycin was used as positive control)
In HepG2 and Hep3B cells transfected with LC3–GFP, ApoG2-induced autophagy is evident by a punctate pattern of green-fluorescent LC3–GFP (Figure 1d, white arrows), whereas the DMSO control cells exhibited diffuse LC3-associated green fluorescence
Summary
The anti-apoptotic Bcl-2 family proteins consist of Bcl-2, Bcl-xL, Mcl-1, A1 and Bcl-W, which are generally integrated within the outer mitochondrial membrane.[5] Overexpressed and dysregulated, anti-apoptotic Bcl-2 proteins are seen in various tumor types, such as prostate, non-Hodgkin’s lymphoma, colorectal, breast, non-small cell lung cancer and HCC.[6] Abundant evidence has shown that suppression of anti-apoptotic Bcl-2 proteins is a feasible strategy for cancer therapy.[7]. We demonstrate that the suppression of autophagy using antioxidants enhances cell death induced by ApoG2, suggesting a new approach for combinational therapy in treating HCC
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