title: Lipin-1 regulation of phospholipid synthesis maintains endoplasmic reticulum homeostasis and is critical for triple-negative breast cancer cell survival.
abstract: Cancer cells reprogram their metabolism to increase the synthesis of macromolecules for rapid proliferation. Compared to fatty acids, much less is known about the synthesis of phospholipids, which is essential for membrane biogenesis in cancer cells. We found thatLPIN1, which encodes lipin-1, a phosphatidic acid phosphatase (PAP) controlling the rate-limiting step in the phospholipid synthesis pathway, is highly up-regulated in basal-like triple-negative breast cancer (TNBC). Moreover, highLPIN1expression correlates with the poor prognosis of these patients. Knockdown ofLPIN1increases apoptosis in basal-like TNBC cell lines, whereas it has minimal or less effect on normal human mammary gland epithelial cells (HMECs) and estrogen receptor-positive breast cancer cell lines. Fatty acid incorporation and lipidomics analyses showed thatLPIN1knockdown blocks phospholipid synthesis and changes membrane lipid compositions that ultimately induce the activation of 1 of the 3 branches of unfolded protein responses, the inositol-requiring enzyme-1α pathway. We also show for the first time, to our knowledge, that lipin-1 knockdown significantly inhibits tumor growthin vivousing an orthotopic xenograft breast mouse model. Our results suggest that lipin-1 is a potential target for cancer therapy.-He, J., Zhang, F., Tay, L. W. R., Boroda, S., Nian, W., Levental, K. R., Levental, I., Harris, T. E., Chang, J. T., Du, G. Lipin-1 regulation of phospholipid synthesis maintains endoplasmic reticulum homeostasis and is critical for triple-negative breast cancer cell survival.
authors.affiliation: Department of Integrative Biology and Pharmacology University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Jingquan
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Integrative Biology and Pharmacology University of Texas Health Science Center at Houston, Houston, Texas, USA.|Core Facility, Department of Clinical Laboratory, Quzhou People's Hospital, Quzhou, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Integrative Biology and Pharmacology University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Li Wei Rachel
authors.initials: LWR
authors.lastname: Tay
authors.affiliation: Department of Pharmacology, University of Virginia Health System, Charlottesville, Virginia, USA.
authors.forename: Salome
authors.initials: S
authors.lastname: Boroda
authors.affiliation: Department of Integrative Biology and Pharmacology University of Texas Health Science Center at Houston, Houston, Texas, USA.|Key Laboratory of Oncology, Chongqing Cancer Hospital and Institute and Cancer Center, Chongqing, China.
authors.forename: Weiqi
authors.initials: W
authors.lastname: Nian
authors.affiliation: Department of Integrative Biology and Pharmacology University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Kandice R
authors.initials: KR
authors.lastname: Levental
authors.affiliation: Department of Integrative Biology and Pharmacology University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Ilya
authors.initials: I
authors.lastname: Levental
authors.affiliation: Department of Pharmacology, University of Virginia Health System, Charlottesville, Virginia, USA.
authors.forename: Thurl E
authors.initials: TE
authors.lastname: Harris
authors.affiliation: Department of Integrative Biology and Pharmacology University of Texas Health Science Center at Houston, Houston, Texas, USA.|School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Chang
authors.affiliation: Department of Integrative Biology and Pharmacology University of Texas Health Science Center at Houston, Houston, Texas, USA; guangwei.du@uth.tmc.edu.
authors.forename: Guangwei
authors.initials: G
authors.lastname: Du
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000473:pathology; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism*; D010743:Phospholipids / Q000096:biosynthesis*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D010743:Phospholipids; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C546842:MTOR protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D004722:Endoribonucleases; C485999:LPIN1 protein, human; D010711:Phosphatidate Phosphatase
keywords: IRE1α; LPIN1; TNBC; endoplasmic reticulum stress; membrane biogenesis