title: Chemotherapy-induced apoptosis in hepatocellular carcinoma involves the p53 family and is mediated via the extrinsic and the intrinsic pathway.
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.
authors.affiliation: Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Seitz
authors.forename: Elisa Schulze
authors.initials: ES
authors.lastname: Schleithoff
authors.forename: Andreas
authors.initials: A
authors.lastname: Koch
authors.forename: André
authors.initials: A
authors.lastname: Schuster
authors.forename: Andreas
authors.initials: A
authors.lastname: Teufel
authors.forename: Frank
authors.initials: F
authors.lastname: Staib
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.forename: Tobias
authors.initials: T
authors.lastname: Schilling
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001761:Bleomycin / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D020169:Caspases / Q000502:physiology; D053200:Fas-Associated Death Domain Protein / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: C081876:CKAP4 protein, human; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; D001761:Bleomycin; D020169:Caspases