Etoposide induces a mixed type of programmed cell death and overcomes the resistance conferred by Bcl-2 in Hep3B hepatoma cells

Abstract

Abstract. The Bcl-2 protein is known to exert not only antiapoptotic but also anti-autophagic activities. Numerous studies have demonstrated that etoposide, which is one of the most widely used cancer chemotherapy agents, induces apoptotic cell death. However, the exact molecular mechanism leading to cell death by etoposide remains to be resolved. This study aimed to dissect the mode of cell death induced by etoposide in Hep3B hepatoma cells. Furthermore, this study was conducted to examine whether etoposide overcomes the resistance conferred by Bcl-2 in Hep3B hepatoma cells. We observed that Hep3B cells treated with etoposide show not only apoptotic but autophagic phenotypes. Autophagy inhibition by 3-methyladenine (3MA) and caspase inhibition by zVAD-fmk effectively decreased autophagic and apoptotic phenotypes, respectively. However, either zVAD-fmk or 3MA only partially prevented cell death. These data indicate that etoposide concomitantly induces autophagic cell death and apoptosis in Hep3B cells. Importantly, etoposide can effectively induce cell death in Bcl-2-overexpressing Hep3B cells. Conversely, staurosporine, which exclusively induces apoptosis in Hep3B cells, did not efficiently induce cell death in Bcl-2-overexpressing Hep3B cells. Staurosporine-treated Hep3B cells also showed an autophagic phenotype. While autophagy is cell death-inducing in Hep3B cells treated with etoposide, it is cytoprotective in Hep3B cells treated with staurosporine. To this end, we observed that etoposide-induced mixed type of programmed cell death is associated with the dissociation of Bcl-2 from Beclin-1. Taken together, etoposide induces a mixed type of programmed cell death and overcomes the resistance conferred by Bcl-2 in Hep3B hepatoma cells.

C10ORF10/DEPP-mediated ROS accumulation is a critical modulator of FOXO3-induced autophagy

“…Both chemotherapeutic agents induce autophagy and autophagic flux in neuroblastoma (Fig. 7b and Additional file 5) similar to what has been published for other cancer types [69, 70]. The idea that autophagic processes are essential for eliminating damaged proteins and organelles to preserve tumor cell life also during chemotherapy was further supported by using the autophagy-inhibitor CQ that significantly enhanced the chemotherapeutic effect of etoposide and doxorubicin in SH-EP and NB15 cells (Fig.…”

Mechanism of autophagic regulation in carcinogenesis and cancer therapeutics

“…Additionally, the class of toposiomerase II inhibitors forms an active class of therapeutics that mediate an autophagic cell deathinducing response to curb the malignancy. The anti-leukemic drug amsacrine induces autophagy along with a concomitant decrease in p62 expression, while etoposide induces autophagic death by dissociating Bcl-2 from the Beclin-1 complex in Hep3B hepatoma cells [70,71]. The FDA-approved anti-glioma, DNA alkylating agent temozolomide serves as the most effective treatment for patients with different stages of astrocytoma, and it is a very powerful autophagic cell death-inducing drug [72].…”

Correlation and prognostic value of osteopontin and Bcl-2 in hepatocellular carcinoma patients after curative resection

“…OPN could inhibit the apoptosis of adherent endothelial cells induced by growth factors and cytokine depletion by enhancing Bcl-xL expression (2). Bcl-2 has been demonstrated to play important roles in the development and progression of several types of cancer (3)(4)(5), and can be an independent predictor of cancer outcome (6,7). Bcl-2 has also been found to play an important role in resistance to 5-fluorouracil-caused cell death of hepatocellular carcinoma (HCC) (8).…”