Metformin sensitizes triple-negative breast cancer to proapoptotic TRAIL receptor agonists by suppressing XIAP expression.
OBJECTIVE
Despite robust antitumor activity in diverse preclinical models, TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists have not demonstrated efficacy in clinical trials, underscoring the need to identify agents that enhance their activity. We postulated that the metabolic stress induced by the diabetes drug metformin would sensitize breast cancer cells to TRAIL receptor agonists.


METHODS
Human triple (estrogen receptor, progesterone receptor, and HER2)-negative breast cancer (TNBC) cell lines were treated with TRAIL receptor agonists (monoclonal antibodies or TRAIL peptide), metformin, or the combination. The effects on cell survival, caspase activation, and expression of TRAIL receptors and the antiapoptotic protein XIAP were determined. In addition, XIAP was silenced by RNAi in TNBC cells and the effects on sensitivity to TRAIL were determined. The antitumor effects of metformin, TRAIL, or the combination were evaluated in an orthotopic model of metastatic TNBC.


RESULTS
Metformin sensitized diverse TNBC cells to TRAIL receptor agonists. Metformin selectively enhanced the sensitivity of transformed breast epithelial cells to TRAIL receptor agonist-induced caspase activation and apoptosis with little effect on untransformed breast epithelial cells. These effects of metformin were accompanied by robust reductions in the protein levels of XIAP, a negative regulator of TRAIL-induced apoptosis. Silencing XIAP in TNBC cells mimicked the TRAIL-sensitizing effects of metformin. Metformin also enhanced the antitumor effects of TRAIL in a metastatic murine TNBC model.


CONCLUSIONS
Our findings indicate that metformin enhances the activity of TRAIL receptor agonists, thereby supporting the rationale for additional translational studies combining these agents.
Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, MFCB 4144, 1685 Highland Avenue, Madison, WI, 53705, USA.
Elena
E
Strekalova
Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, MFCB 4144, 1685 Highland Avenue, Madison, WI, 53705, USA.
Dmitry
D
Malin
Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, MFCB 4144, 1685 Highland Avenue, Madison, WI, 53705, USA.
Harisha
H
Rajanala
Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, MFCB 4144, 1685 Highland Avenue, Madison, WI, 53705, USA. vlcryns@medicine.wisc.edu.
Vincent L
http://orcid.org/0000-0003-0355-2268
VL
Cryns
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D034622:RNA Interference; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D008687:Metformin; D020169:Caspases
Apoptosis; Breast cancer; Metastasis; Metformin; TRAIL; Therapeutics