Upregulation of endogenous TRAIL-elicited apoptosis is essential for metformin-mediated antitumor activity against TNBC and NSCLC

Shuang Liu; Erik V Polsdofer; Lukun Zhou; Sanbao Ruan; Hui Lyu; Defu Hou; Hao Liu; Ann D Thor; Zhimin He; Bolin Liu

doi:10.1016/j.omto.2021.04.012

Upregulation of endogenous TRAIL-elicited apoptosis is essential for metformin-mediated antitumor activity against TNBC and NSCLC

Mol Ther Oncolytics. 2021 Apr 29:21:303-314. doi: 10.1016/j.omto.2021.04.012. eCollection 2021 Jun 25.

Authors

Shuang Liu^{1

2}, Erik V Polsdofer³, Lukun Zhou², Sanbao Ruan², Hui Lyu², Defu Hou², Hao Liu², Ann D Thor³, Zhimin He¹, Bolin Liu²

Affiliations

¹ Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong 510095, China.
² Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA 70112, USA.
³ Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promising antitumor activity in preclinical studies. However, the efficacy of recombinant TRAIL in clinical trials is compromised by its short serum half-life and low in vivo stability. Induction of endogenous TRAIL may overcome the limitations and become a new strategy for cancer treatment. Here, we discovered that metformin increased TRAIL expression and induced apoptosis in triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) cells. Metformin did not alter the expression of TRAIL receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). Metformin-upregulated TRAIL was secreted into conditioned medium (CM) and found to be functional, since the CM promoted TNBC cells undergoing apoptosis, which was abrogated by a recombinant TRAIL-R2-Fc chimera. Moreover, blockade of TRAIL binding to DR4/DR5 or specific knockdown of TRAIL expression significantly attenuated metformin-induced apoptosis. Studies with a tumor xenograft model revealed that metformin not only significantly inhibited tumor growth but also elicited apoptosis and enhanced TRAIL expression in vivo. Collectively, we have demonstrated that upregulation of TRAIL and activation of death receptor signaling are pivotal for metformin-induced apoptosis in TNBC and NSCLC cells. Our studies identify a novel mechanism of action of metformin exhibiting potent antitumor activity via induction of endogenous TRAIL.

Keywords: NSCLC; TNBC; TRAIL; apoptosis; metformin.