Lipin-1 regulates cancer cell phenotype and is a potential target to potentiate rapamycin treatment

Lipogenesis inhibition was reported to induce apoptosis and repress proliferation
of cancer cells while barely affecting normal cells. Lipins exhibit dual function as
enzymes catalyzing the dephosphorylation of phosphatidic acid to diacylglycerol and
as co-transcriptional regulators. Thus, they are able to regulate lipid homeostasis at
several nodal points. Here, we show that lipin-1 is up-regulated in several cancer cell
lines and overexpressed in 50 % of high grade prostate cancers. The proliferation
of prostate and breast cancer cells, but not of non-tumorigenic cells, was repressed
upon lipin-1 knock-down. Lipin-1 depletion also decreased cancer cell migration
through RhoA activation. Lipin-1 silencing did not significantly affect global lipid
synthesis but enhanced the cellular concentration of phosphatidic acid. In parallel,
autophagy was induced while AKT and ribosomal protein S6 phosphorylation were
repressed. We also observed a compensatory regulation between lipin-1 and lipin-2
and demonstrated that their co-silencing aggravates the phenotype induced by
lipin-1 silencing alone. Most interestingly, lipin-1 depletion or lipins inhibition with
propranolol sensitized cancer cells to rapamycin. These data indicate that lipin-1
controls main cellular processes involved in cancer progression and that its targeting,
alone or in combination with other treatments, could open new avenues in anticancer
therapy.