Autophagy induction causes a synthetic lethal sensitization to ribonucleotide reductase inhibition in breast cancer cells
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Yun-Ru Chen1,2, Brittany Tsou1,2, Shuya Hu1, Huimin Ma1,2, Xiyong Liu1, Yun Yen1 and David K. Ann1,2
1 Department of Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
2 Department of Diabetes and Metabolic Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
Yun Yen, email:
David K. Ann, email:
Keywords: autophagy, ribonucleotide reductase, synthetic lethality, breast cancer, tamoxifen
Received: June 22, 2015 Accepted: November 21, 2015 Published: December 09, 2015
Macroautophagy can promote cellular survival or death depending on the cellular context and its extent. We hypothesized that autophagy induction would synergize with a therapeutic agent targeting the autophagic cargo. To test this hypothesis, we treated breast cancer MDA-MB-231 cells with tamoxifen (TMX), which induces autophagy through an estrogen receptor-independent pathway. Induction of autophagy reduced cellular levels of RRM2, a subunit of ribonucleotide reductase (RR), the rate limiting enzyme in the production of deoxyribonucleotide triphosphates (dNTPs). This autophagy inducer was combined with COH29, an inhibitor developed in our laboratory that targets RR through a novel mechanism. The combination therapy showed synergistic effects on cytotoxicity in vitro and in an in vivo xenograft model. This cytotoxicity was blocked by knockdown of the autophagy protein ATG5 or addition of chloroquine, an autophagy inhibitor. The combined therapy also induced dNTP depletion and massive genomic instability, leading us to hypothesize that combining autophagy induction with RR inhibition can lead to mitotic catastrophe in rapidly dividing cells. We propose that this TMX + COH29 combined therapy may have clinical benefit. Furthermore, autophagy induction may be a general mechanism for augmenting the effects of chemotherapeutic agents
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