title: Autophagy induction causes a synthetic lethal sensitization to ribonucleotide reductase inhibition in breast cancer cells.
abstract: 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.
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.|Department of Diabetes and Metabolic Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Yun-Ru
authors.initials: YR
authors.lastname: Chen
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.|Department of Diabetes and Metabolic Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Tsou
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Shuya
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.|Department of Diabetes and Metabolic Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Huimin
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Xiyong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.|Department of Diabetes and Metabolic Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Ann
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012262:Ribonucleoside Diphosphate Reductase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000962:Antimalarials; D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; C000599194:N-(4-(3,4-dihydroxyphenyl)-5-phenylthiazol-2-yl)-3,4-dihydroxybenzamide; D012333:RNA, Messenger; D013844:Thiazoles; D013629:Tamoxifen; D002738:Chloroquine; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase
keywords: autophagy; breast cancer; ribonucleotide reductase; synthetic lethality; tamoxifen