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Translational Regulation of X-Linked Inhibitor of Apoptosis Protein by Interleukin-6

A Novel Mechanism of Tumor Cell Survival

¹ Scott and White Clinic, Texas A&M University System Health Science Center College of Medicine, Temple, Texas, and ² Solange Gauthier Karsh Molecular Genetics Laboratory, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada

Interleukin-6 (IL-6) is a pleiotropic cytokine with diverse biological effects. IL-6 has been implicated in autocrine signaling pathways promoting tumor progression and chemoresistance in some human tumors. However, the mechanisms by which IL-6 modulates these responses are unknown. Aberrant apoptosis has been implicated as a fundamental mechanism of chemotherapeutic resistance. Thus, we investigated whether IL-6 alters the expression of apoptosis regulatory proteins as a mechanism of drug resistance. We provide evidence that IL-6 rapidly phosphorylates the translation initiation factor eukaryotic initiation factor-4E and triggers antiapoptotic responses in cholangiocarcinoma cells. Reduction of cellular eukaryotic initiation factor-4E by RNA interference decreases IL-6-induced effects on cytotoxic drug-induced caspase activation and apoptosis. Furthermore, IL-6 increases expression of the endogenous X-linked inhibitor of apoptosis protein expression by translation at an internal ribosome entry site. Our findings that IL-6 translationally regulates X-linked inhibitor of apoptosis protein expression reveal a novel mechanism by which IL-6 mediates tumor cell survival that may be targeted therapeutically to decrease tumor progression and chemoresistance.

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