DNA Damage and Repair Mcl-1 Mediates TWEAK/Fn14-Induced Non–Small Cell Lung Cancer Survival and Therapeutic Response

Abstract

Insensitivity to standard clinical interventions, including chemotherapy, radiotherapy, and tyrosine kinase inhibitor (TKI) treatment, remains a substantial hindrance towards improving the prognosis of patients with non– small cell lung cancer (NSCLC). The molecular mechanism of therapeutic resistance remains poorly understood. The TNF-like weak inducer of apoptosis (TWEAK)–FGF-inducible 14 (TNFRSF12A/Fn14) signaling axis is known to promote cancer cell survival via NF-kB activation and the upregulation of prosurvival Bcl-2 family members. Here, a role was determined for TWEAK–Fn14 prosurvival signaling in NSCLC through the upregulation of myeloid cell leukemia sequence 1 (MCL1/Mcl-1). Mcl-1 expression significantly correlated with Fn14 expression, advanced NSCLC tumor stage, and poor patient prognosis in human primary NSCLC tumors. TWEAK stimulation of NSCLC cells inducedNF-kB–dependentMcl-1 protein expression and conferredMcl-1– dependent chemoand radioresistance. Depletion ofMcl-1 via siRNA or pharmacologic inhibition ofMcl-1, using EU-5148, sensitized TWEAK-treated NSCLC cells to cisplatinor radiation-mediated inhibition of cell survival. Moreover, EU-5148 inhibited cell survival across a panel of NSCLC cell lines. In contrast, inhibition of Bcl-2/BclxL function had minimal effect on suppressing TWEAK-induced cell survival. Collectively, these results position TWEAK–Fn14 signaling throughMcl-1 as a significant mechanism for NSCLC tumor cell survival and open new therapeutic avenues to abrogate the high mortality rate seen in NSCLC. Implications: The TWEAK–Fn14 signaling axis enhances lung cancer cell survival and therapeutic resistance through Mcl-1, positioning both TWEAK–Fn14 and Mcl-1 as therapeutic opportunities in lung cancer. Mol Cancer Res; 12(4); 550–9. 2014 AACR.

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Cite this paper

@inproceedings{Whitsett2014DNADA, title={DNA Damage and Repair Mcl-1 Mediates TWEAK/Fn14-Induced Non–Small Cell Lung Cancer Survival and Therapeutic Response}, author={Timothy G. Whitsett and Ian T. Mathews and Michael H. Cardone and Ryan J. Lena and William E. Pierceall and Michael Bittner and Chao Sima and Janine LoBello and Glen J. Weiss and Nhan Tran}, year={2014} }