title: GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity.
abstract: Breast cancers possess fundamentally altered metabolism that fuels their pathogenicity. While many metabolic drivers of breast cancers have been identified, the metabolic pathways that mediate breast cancer malignancy and poor prognosis are less well understood. Here, we used a reactivity-based chemoproteomic platform to profile metabolic enzymes that are enriched in breast cancer cell types linked to poor prognosis, including triple-negative breast cancer (TNBC) cells and breast cancer cells that have undergone an epithelial-mesenchymal transition-like state of heightened malignancy. We identified glutathione S-transferase Pi 1 (GSTP1) as a novel TNBC target that controls cancer pathogenicity by regulating glycolytic and lipid metabolism, energetics, and oncogenic signaling pathways through a protein interaction that activates glyceraldehyde-3-phosphate dehydrogenase activity. We show that genetic or pharmacological inactivation of GSTP1 impairs cell survival and tumorigenesis in TNBC cells. We put forth GSTP1 inhibitors as a novel therapeutic strategy for combatting TNBCs through impairing key cancer metabolism and signaling pathways.
authors.affiliation: Departments of Chemistry and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Louie
authors.affiliation: Departments of Chemistry and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grossman
authors.affiliation: Department of Chemistry, Boston College, Chestnut Hill, MA 02467, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Crawford
authors.affiliation: Departments of Chemistry and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Lucky
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Cell and Tissue Biology and Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Camarda
authors.affiliation: Departments of Chemistry and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Tucker R
authors.initials: TR
authors.lastname: Huffman
authors.affiliation: Departments of Chemistry and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Miyamoto
authors.affiliation: Department of Cell and Tissue Biology and Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Andrei
authors.initials: A
authors.lastname: Goga
authors.affiliation: Department of Chemistry, Boston College, Chestnut Hill, MA 02467, USA.
authors.forename: Eranthie
authors.initials: E
authors.lastname: Weerapana
authors.affiliation: Departments of Chemistry and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: dnomura@berkeley.edu.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C000624392:LAS17 compound; D014227:Triazines; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D007930:Leucine