Chemotherapy-induced apoptosis in hepatocellular carcinoma (HCC) involves activation of the p53 family and is mediated by signaling via death receptors and mitochondria

Abstract

In HCC patients, conventional chemo- and radiation therapy fail. This failure is mainly due to resistance towards apoptosis. Therefore, current attempts to improve the survival of HCC patients will have to include strategies that specifically target tumor cell resistance towards apoptosis. However, the molecular determinants, which confer resistance of HCC cells towards chemotherapeutic agents, have not yet been fully elucidated. We investigated the mechanisms by which chemotherapeutic drugs elicit apoptosis in hepatocellular carcinoma. DNA damaging agents induce accumulation and activation of all three p53 family members, p53, p63 and p73. Endogenous p53, p63 and p73 were upregulated in response to DNA damage by chemotherapeutic drugs. Stimulation and blocking experiments of the CD95-, the TNF- and the TRAIL- receptor systems revealed that cytotoxic drugs via the p53 family member as transactivators can trigger expression of each of these death receptors and sensitize tumor cells towards apoptosis. Furthermore, our findings demonstrate a link between chemotherapy, the p53 family and the mitochondrial apoptosis pathway in HCC. Chemotherapeutic treatment upregulates expression of proapoptotic Bcl-2 family members like Bax and BCL2L11 and the expression of APAF1, BNIP1, PDCD8 and RAD. Thus, cytostatic drugs engage both, the extrinsic apoptosis pathway initiated by ligation of death receptors and the intrinsic/mitochondrial apoptosis pathway. Of clinical relevance is the fact that blocking p53 family function leads to chemoresistance in HCC. In addition, not only proapoptotic genes were upregulated but also genes known to exert antiapoptotic functions. Bleomycin-induced upregulation of antiapoptotic BCL-XL/BCLXL1 and of the p53 antagonist MDM2 suggest that it is the ratio of pro- and antiapoptotic proteins which regulates the apoptosis response of cancer cells towards chemotherapy, thereby playing a decisive role between treatment sensitivity vs. drug resistance.