title: hnRNP K suppresses apoptosis independent of p53 status by maintaining high levels of endogenous caspase inhibitors.
abstract: Hepatocellular carcinoma (HCC) is the third highest cause of cancer-related deaths globally. One of the cellular hallmarks of this disease is dysregulation of apoptosis, and a better understanding of this process is important if progress is to be made toward effectively treating HCC. Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a RNA-binding protein that is implicated in apoptosis and is upregulated in various cancers, including HCC. In this study, we report new evidence for a crucial role of hnRNP K in suppressing apoptosis in HCC cells. We used the chemotherapeutic agent 5-fluorouracil to induce apoptosis in HCC cell lines and found that hnRNP K was downregulated, independent of both p53 and caspases. Prolonged downregulation of hnRNP K using small interfering RNA (siRNA) significantly decreased cell viability and increased apoptosis in HCC cell lines in a p53-independent manner. Moreover, enhanced tumor necrosis factor-related apoptosis-inducing ligand potency, independent of BH3-interacting domain death agonist (BID) cleavage, was also observed in hnRNP K siRNA-treated cells. Examination of the underlying mechanism revealed that hnRNP K suppresses the activity of various caspases through controlling transcription of the caspase inhibitor XIAP. Taken together, this study establishes that hnRNP K plays an antiapoptotic role in HCC cell lines, independent of p53 status, via the maintenance of high levels of endogenous caspase inhibitors, and also identifies hnRNP K as a possible therapeutic marker for cancer treatment.
authors: Singapore Immunology Network, A*STAR, 8A Biomedical Grove, #03-06, Immunos, Singapore 138648, Singapore.
authors: Ziwei
authors: Z
authors: Xiao
authors: Hui Ling
authors: HL
authors: Ko
authors: Ee Hui
authors: EH
authors: Goh
authors: Bei
authors: B
authors: Wang
authors: Ee Chee
authors: EC
authors: Ren
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D056945:Hep G2 Cells; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology*; D016297:Mutagenesis, Site-Directed; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C505407:CASP3 protein, human; D053148:Caspase 3; D005472:Fluorouracil