AMPK Activation and Metabolic Reprogramming by Tamoxifen through Estrogen Receptor-Independent Mechanisms Suggests New Uses for This Therapeutic Modality in Cancer Treatment

作者：Daurio Natalie A; Tuttle Stephen W; Worth Andrew J; Song Ethan Y; Davis Julianne M; Snyder Nathaniel W; Blair Ian A; Koumenis Constantinos^*

来源：Cancer Research, 2016, 76(11): 3295-3306.

DOI：10.1158/0008-5472.CAN-15-2197

Tamoxifen is the most widely used adjuvant chemotherapeutic for the treatment of estrogen receptor (ER)-positive breast cancer, yet a large body of clinical and preclinical data indicates that tamoxifen can modulate multiple cellular processes independently of ER status. Here, we describe the ER-independent effects of tamoxifen on tumor metabolism. Using combined pharmacologic and genetic knockout approaches, we demonstrate that tamoxifen inhibits oxygen consumption via inhibition of mitochondrial complex I, resulting in an increase in the AMP/ATP ratio and activation of the AMP-activated protein kinase (AMPK) signaling pathway in vitro and in vivo. AMPK in turn promotes glycolysis and alters fatty acid metabolism. We also show that tamoxifen-induced cytotoxicity is modulated by isoform-specific effects of AMPK signaling, in which AMPKa1 promotes cell death through inhibition of the mTOR pathway and translation. By using agents that concurrently target distinct adaptive responses to tamoxifen-mediated metabolic reprogramming, we demonstrate increased cytotoxicity through synergistic therapeutic approaches. Our results demonstrate novel metabolic perturbations by tamoxifen in tumor cells, which can be exploited to expand the therapeutic potential of tamoxifen treatment beyond ER+ breast cancer.

• 出版日期2016-6-1