Regulation of glutamine carrier proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies.

Abstract

Many tumor cells are fueled by altered metabolism and increased glutamine (Gln) dependence. We identify regulation of the L-glutamine carrier proteins SLC1A5 and SLC38A2 (SLC1A5/38A2) by the ubiquitin ligase RNF5. Paclitaxel-induced ER stress to breast cancer (BCa) cells promotes RNF5 association, ubiquitination, and degradation of SLC1A5/38A2. This decreases Gln uptake, levels of TCA cycle components, mTOR signaling, and proliferation while increasing autophagy and cell death. Rnf5-deficient MMTV-PyMT mammary tumors were less differentiated and showed elevated SLC1A5 expression. Whereas RNF5 depletion in MDA-MB-231 cells promoted tumorigenesis and abolished paclitaxel responsiveness, SLC1A5/38A2 knockdown elicited opposing effects. Inverse RNF5(hi)/SLC1A5/38A2(lo) expression was associated with positive prognosis in BCa. Thus, RNF5 control of Gln uptake underlies BCa response to chemotherapies.

• Authors: Young Joo Jeon, Sihem Khelifa, Boris Ratnikov, David A Scott, Yongmei Feng, Fabio Parisi, Chelsea Ruller, Eric Lau, Hyungsoo Kim, Laurence M Brill, Tingting Jiang, David L Rimm, Robert D Cardiff, Gordon B Mills, Jeffrey W Smith, Andrei L Osterman, Yuval Kluger, Ze'ev A Ronai
• Journal: Cancer cell (Cancer Cell) Vol. 27 Issue 3 Pg. 354-69 (Mar 09 2015) ISSN: 1878-3686 [Electronic] United States
• PMID: 25759021 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Amino Acid Transport System A
• Amino Acid Transport System ASC
• Antineoplastic Agents
• DNA-Binding Proteins
• Minor Histocompatibility Antigens
• SLC1A5 protein, human
• SLC38A2 protein, human
• RNF5 protein, human
• Ubiquitin-Protein Ligases
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Paclitaxel

Topics

• Amino Acid Transport System A (genetics, metabolism)
• Amino Acid Transport System ASC (genetics, metabolism)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Citric Acid Cycle (drug effects)
• DNA-Binding Proteins (genetics, metabolism, physiology)
• Endoplasmic Reticulum (drug effects)
• Endoplasmic Reticulum Stress (drug effects, genetics)
• Female
• Humans
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Nude
• Minor Histocompatibility Antigens
• Paclitaxel (pharmacology, therapeutic use)
• Proteolysis (drug effects)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism, physiology)
• Ubiquitination