Lipin-1 regulates cancer cell phenotype and is a potential target to amplify the effect of metabolic inhibitors

An increased lipogenesis was reported in various cancers and its inhibition represses proliferation and induces apoptosis of cancer cells while barely affecting most normal cells. The family of lipins encompasses three members: lipin-1, -2 and -3. All exhibit dual functions as enzymes, catalyzing the de-phosphorylation of phosphatidic acid to diacylglycerol, and as co-transcriptional regulators. Thus, they are able to regulate lipid homeostasis at several nodal points. However, no studies addressed the involvement of these proteins in cancer progression neither in vitro nor in vivo.
During this PhD work, we first investigated the importance of lipin-1 on prostate cancer cell phenotype. We showed that lipin-1 expression is increased in various cancer cell types both in vitro and in vivo in human prostate tumor samples. The specific inhibition of lipin-1 in prostate and breast cancer cells demonstrated its critical importance for cell proliferation and migration through deregulation of several intracellular signaling pathways. This study demonstrated for the first time that the targeting of lipin-1 is a potential new anti-cancer strategy that could be used alone or in combination with drugs like rapamycin. During the course of these investigations, we also observed a compensatory regulation between lipin-1 and lipin-2 preventing the complete inhibition of lipins enzymatic activity when using a siRNA approach. Therefore, we focused our interest on inhibiting all lipins through treatment with a pharmacological inhibitor, propranolol. This drug also induced a blockade of the late phases of autophagy, likely because the inhibition of all lipins decreases diacylglycerol synthesis, which is required for the maturation of autolysosomes.
Autophagy is a pro-survival mechanism induced by several stresses or by anticancer agents. In the case of the glycolysis inhibitor 2DG, the induction of autophagy limits its anticancer effects in monotherapy. In the light of their individual specific effects on cancer cells, we hypothesized that the combination of propranolol and 2DG might exert a more than additive toxic effect on cancer cells. In this second study, we report that combined treatment is effective on preventing prostate cancer cell proliferation, inducing cell apoptosis, altering the function of several organelles as mitochondria, endoplasmic reticulum and Golgi apparatus in vitro but also in suppressing tumor growth in vivo.
Altogether, our data suggest that lipins are key players involved in cancer progression. Targeting lipins, alone or in combination with other treatments, could open new avenues in anticancer therapy.