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: Ziwei Xiao, Hui Ling Ko, Ee Hui Goh, Bei Wang, Ee Chee Ren
• Journal: Carcinogenesis (Carcinogenesis) Vol. 34 Issue 7 Pg. 1458-67 (Jul 2013) ISSN: 1460-2180 [Electronic] England
• PMID: 23455382 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BH3 Interacting Domain Death Agonist Protein
• BID protein, human
• Heterogeneous-Nuclear Ribonucleoprotein K
• RNA, Small Interfering
• TP53 protein, human
• Tumor Suppressor Protein p53
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human
• CASP3 protein, human
• Caspase 3
• Fluorouracil

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• BH3 Interacting Domain Death Agonist Protein (genetics, metabolism)
• Carcinoma, Hepatocellular (enzymology, pathology)
• Caspase 3 (genetics, metabolism)
• Cell Survival (drug effects)
• Fluorouracil (pharmacology)
• Gene Expression Regulation, Neoplastic
• HCT116 Cells
• Hep G2 Cells
• Heterogeneous-Nuclear Ribonucleoprotein K (genetics, metabolism)
• Humans
• Liver Neoplasms (enzymology, pathology)
• Mutagenesis, Site-Directed
• Proteolysis
• RNA, Small Interfering (genetics, metabolism)
• Transfection
• Tumor Suppressor Protein p53 (genetics, metabolism)
• X-Linked Inhibitor of Apoptosis Protein (genetics, metabolism)