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

Cancer Cell. 2015 Mar 9;27(3):354-69. doi: 10.1016/j.ccell.2015.02.006.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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