title: 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.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06510, USA.
authors.forename: Sihem
authors.initials: S
authors.lastname: Khelifa
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Ratnikov
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06510, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Parisi
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Ruller
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lau
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Hyungsoo
authors.initials: H
authors.lastname: Kim
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Laurence M
authors.initials: LM
authors.lastname: Brill
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06510, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06510, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.affiliation: Department of Pathology, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Cardiff
authors.affiliation: Department of Systems Biology, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Smith
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Osterman
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06510, USA.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Kluger
authors.affiliation: Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA. Electronic address: ronai@sbmri.org.
authors.forename: Ze'ev A
authors.initials: ZA
authors.lastname: Ronai
mesh_terms: D026924:Amino Acid Transport System A / Q000235:genetics / Q000378:metabolism*; D026962:Amino Acid Transport System ASC / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002952:Citric Acid Cycle / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D015778:Minor Histocompatibility Antigens; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D059748:Proteolysis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D026924:Amino Acid Transport System A; D026962:Amino Acid Transport System ASC; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D015778:Minor Histocompatibility Antigens; C420506:SLC1A5 protein, human; C498797:SLC38A2 protein, human; C111501:RNF5 protein, human; D044767:Ubiquitin-Protein Ligases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D017239:Paclitaxel