Chemotherapy-induced apoptosis in hepatocellular carcinoma involves the p53 family and is mediated via the extrinsic and the intrinsic pathway
Sarah J. Seitz
Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany
Search for more papers by this authorElisa Schulze Schleithoff
Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany
Search for more papers by this authorAndreas Koch
Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany
Search for more papers by this authorAndré Schuster
Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany
Search for more papers by this authorAndreas Teufel
Department of Internal Medicine I, University Hospital, Mainz, Germany
Search for more papers by this authorFrank Staib
Department of Internal Medicine I, University Hospital, Mainz, Germany
Search for more papers by this authorWolfgang Stremmel
Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany
Search for more papers by this authorGerry Melino
Biochemistry Laboratory, IDI-IRCCS, c/o Department of Experimental Medicine and Biochemical Sciences, University of Rome, 00133 Rome, Italy
Medical Research Council, Toxicology Unit, Hodgkin Building, University of Leicester, Leicester, LE1 9HN, United Kingdom
Search for more papers by this authorPeter H. Krammer
Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorTobias Schilling
Department of Internal Medicine I and Clinical Chemistry, University Hospital, Heidelberg, Germany
The last two authors contributed equally to this work
Search for more papers by this authorCorresponding Author
Martina Müller
Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany
The last two authors contributed equally to this work
Fax: +49-6221-56-4395
Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, GermanySearch for more papers by this authorSarah J. Seitz
Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany
Search for more papers by this authorElisa Schulze Schleithoff
Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany
Search for more papers by this authorAndreas Koch
Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany
Search for more papers by this authorAndré Schuster
Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany
Search for more papers by this authorAndreas Teufel
Department of Internal Medicine I, University Hospital, Mainz, Germany
Search for more papers by this authorFrank Staib
Department of Internal Medicine I, University Hospital, Mainz, Germany
Search for more papers by this authorWolfgang Stremmel
Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany
Search for more papers by this authorGerry Melino
Biochemistry Laboratory, IDI-IRCCS, c/o Department of Experimental Medicine and Biochemical Sciences, University of Rome, 00133 Rome, Italy
Medical Research Council, Toxicology Unit, Hodgkin Building, University of Leicester, Leicester, LE1 9HN, United Kingdom
Search for more papers by this authorPeter H. Krammer
Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany
Search for more papers by this authorTobias Schilling
Department of Internal Medicine I and Clinical Chemistry, University Hospital, Heidelberg, Germany
The last two authors contributed equally to this work
Search for more papers by this authorCorresponding Author
Martina Müller
Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany
The last two authors contributed equally to this work
Fax: +49-6221-56-4395
Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, GermanySearch for more papers by this authorFax: +49-6221-56-4395
Abstract
We investigated the downstream mechanisms by which chemotherapeutic drugs elicit apoptosis in hepatocellular carcinoma (HCC). Genomic signatures of HCC cell lines treated with different chemotherapeutic drugs were obtained. Analyses of apoptosis pathways were performed and RNA interference was used to evaluate the role of the p53 family. Endogenous p53, p63 and p73 were upregulated in response to DNA damage by chemotherapeutic drugs. Blocking p53 family function led to chemoresistance in HCC. Stimulation and blocking experiments of the CD95-, the TNF- and the TRAIL-receptor systems revealed that cytotoxic drugs, via the p53 family members as transactivators, can trigger expression of each of these death receptors and consequently sensitize HCC cells toward apoptosis. Furthermore, our findings demonstrate a link between chemotherapy, the p53 family and the mitochondrial apoptosis pathway in HCC. Chemotherapeutic treatment induces expression of proapoptotic Bcl-2 family members like Bax and BCL2L11 and the expression of Apaf1, BNIP1, Pdcd8 and RAD. Thus, upon DNA damage, p53, p63 and p73 promote apoptosis via the extrinsic and the intrinsic signaling pathway. In addition, not only proapoptotic genes were upregulated, but also genes known to exert antiapoptotic functions. Bleomycin-induced upregulation of BCL-XL/BCLXL1 and MDM2 suggests that it is the ratio of proapoptotic and antiapoptotic proteins that regulates the apoptosis response of HCC cells toward chemotherapy, thereby playing a decisive role between treatment sensitivity vs. drug resistance. The clinical importance of these data is evidenced by our finding that the bleomycin target gene signature can predict the prognosis of patients suffering from HCC.
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