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: Yun-Ru Chen, Brittany Tsou, Shuya Hu, Huimin Ma, Xiyong Liu, Yun Yen, David K Ann
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 2 Pg. 1984-99 (Jan 12 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26675256 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Antineoplastic Agents, Hormonal
• Benzamides
• N-(4-(3,4-dihydroxyphenyl)-5-phenylthiazol-2-yl)-3,4-dihydroxybenzamide
• RNA, Messenger
• Thiazoles
• Tamoxifen
• Chloroquine
• ribonucleotide reductase M2
• Ribonucleoside Diphosphate Reductase

Topics

• Animals
• Antimalarials (pharmacology)
• Antineoplastic Agents, Hormonal (pharmacology)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Benzamides (pharmacology)
• Blotting, Western
• Breast Neoplasms (drug therapy, enzymology, pathology)
• Cell Proliferation (drug effects)
• Chloroquine (pharmacology)
• Drug Synergism
• Drug Therapy, Combination
• Female
• Humans
• Immunoenzyme Techniques
• Mice
• Mice, Inbred NOD
• Mice, SCID
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Ribonucleoside Diphosphate Reductase (antagonists & inhibitors, genetics, metabolism)
• Tamoxifen (pharmacology)
• Thiazoles (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays