LPIN1 promotes epithelial cell transformation and mammary tumourigenesis via enhancing insulin receptor substrate 1 stability

Abstract

LPIN1, a phosphatidic acid phosphatase enzyme, dramatically influence tumor progression, however, their mechanism of action is still poorly understood. Here, we demonstrate that LPIN1 enhances the tumour‐promoting function of IRS1 by controlling IRS1 stability. LPIN1 interacts with IRS1 in an IGF‐1‐dependent signalling pathway and inhibits its serine phosphorylation, 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 as well as AP‐1 transcriptional activity. In the syngeneic 4T1 breast cancer model, LPIN1 overexpression increased tumour development. Consistent with these observations, LPIN1 levels were positively correlated with IRS1 expression in human breast cancer. Thus, our results indicate that LPIN1 may be a promising drug target for anticancer therapy.Support or Funding InformationThis research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C2004).