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 (Fn14) signaling axis is known to promote cancer cell survival via NF-κB activation and the up-regulation of pro-survival Bcl-2 family members. Here, a role was determined for TWEAK-Fn14 pro-survival signaling in NSCLC through the up-regulation of myeloid cell leukemia sequence 1 (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 induced NF-κB-dependent Mcl-1 protein expression and conferred Mcl-1-dependent chemo- and radio-resistance. Depletion of Mcl-1 via siRNA or pharmacological inhibition of Mcl-1, using EU-5148, sensitized TWEAK-treated NSCLC cells to cisplatin- or 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/Bcl-xL function had minimal effect on suppressing TWEAK-induced cell survival. Collectively, these results position TWEAK-Fn14 signaling through Mcl-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.

miR-29b Mediates NF-κB Signaling in KRAS-Induced Non–Small Cell Lung Cancers

“…NF-kB activity induced by miR-29b leads to upregulation of antiapoptotic genes, rendering cancer cells insensitive to the extrinsic apoptotic program (39). Expression of BCL2 family members is also induced by NF-kB conferring insensitivity to cisplatin (40). However, it is well established that miR-29b directly targets the antiapoptotic gene MCL1 in lung cancer (41), tipping the balance toward intrinsic apoptosis (Fig.…”

Impaired DNA double‐strand breaks repair by kinesin family member 4A inhibition renders human H1299 non‐small‐cell lung cancer cells sensitive to cisplatin

“…Feng et al, 2017;C. T. Lee et al, 2003;Liu et al, 2007;Luo et al, 2016;Okamura et al, 2012;Qian et al, 2014;Shin, Choi, & Park, 2014;Whitsett et al, 2014;D. W. Wu et al, 2014;Xiao et al, 2017).…”

Bcl‐2 family in non‐small cell lung cancer: its prognostic and therapeutic implications

“…22 Inhibition of Mcl-1 function enhanced chemo-and radio-sensitivity in NSCLC cells. 23 A clinical study detected Mcl-1 protein expression in NSCLC, Mcl-1 was expressed in 38.1% of squamous cell carcinoma and 45.8% of lung adenocarcinoma, but no significant differences of Mcl-1 expression were detected between the two main types of NSCLC. Overexpression of Mcl-1 was significantly associated with high pathological grade (P ¼ 0.022) and lymph node involvement (P ¼ 0.017) and also correlated with poor prognosis of the patient studied.…”

“…The great majority of the reported studies on Mcl‐1 have been in vitro studies and Mcl‐1 has been reported to be critical for the survival of NSCLC cell lines and stem‐like cells in NSCLC showed higher Mcl‐1 expression . Inhibition of Mcl‐1 function enhanced chemo‐ and radio‐sensitivity in NSCLC cells . A clinical study detected Mcl‐1 protein expression in NSCLC, Mcl‐1 was expressed in 38.1% of squamous cell carcinoma and 45.8% of lung adenocarcinoma, but no significant differences of Mcl‐1 expression were detected between the two main types of NSCLC.…”