title: LPIN1 promotes epithelial cell transformation and mammary tumourigenesis via enhancing insulin receptor substrate 1 stability.
abstract: LPIN1 is a protein that exhibits dual functions as a phosphatidic acid phosphatase enzyme in regulation of triglyceride and glycerophospholipid metabolism and a transcriptional coregulator. Through unknown tumour-promoting mechanism, LPIN1 frequently observed in various human cancer cell lines controls main cellular processes involved in cancer progression. Here, we demonstrate that LPIN1 enhances the tumour-promoting function of insulin receptor substrate 1 (IRS1) by controlling IRS1 stability. LPIN1 interacts with IRS1 in an insulin growth factor-1-dependent signalling pathway and inhibits its serine phosphorylation, and thereby eliminating ubiquitin-dependent degradation of IRS1 via proteasomal and lysosomal pathways. Consequently, LPIN1 overexpression increases IRS1 abundance and enhances IRS1's ability to induce epithelial cell proliferation and mammary tumourigenesis. By contrast, depletion or inhibition of LPIN1 in breast cancer cells leads to a decreased IRS1 level, which subsequently inhibits the RAF1-mediated signalling pathway and AP-1 activity. In the syngeneic 4T1 breast cancer model, LPIN1 overexpression increased tumour development, whereas inhibition of LPIN1 and IRS1 suppressed it. Consistent with these observations, LPIN1 levels were positively correlated with IRS1 expression in human breast cancer. Thus, our results indicate a mechanism by which IRS1 expression is increased in breast cancer, and LPIN1 may be a promising drug target for anticancer therapy.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Garam
authors.initials: G
authors.lastname: Kim
authors.affiliation: Department of Pathology, School of Medicine, Chosun University, 309 Philmundaero, Dong-gu, Gwangju 61452, Republic of Korea.
authors.forename: Sung-Chul
authors.initials: SC
authors.lastname: Lim
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Choi
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics*; D010711:Phosphatidate Phosphatase / Q000235:genetics*
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C485999:LPIN1 protein, human; D010711:Phosphatidate Phosphatase