Microsomal triacylglycerol transfer protein (MTP) inhibition, by hypocholesterolemic drug lomitapide, favors tumor growth

LUCCI A; CEBALLOS, MARÍA PAULA; COMANZO C G; HEIT BARBINI FJ; CARRILLO M C; VERA MC; FERRETTI A; QUIROGA A D

Congreso; Reunión Anual Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB); 2019

Microsomal triacylglycerol transfer protein (MTP) locates in the lumen of the endoplasmic reticulum and participates in the secretion of lipids from the liver as very-low-density lipoproteins. There is evidence that MTP might be involved in other cellular processes, including the pathogenesis of different diseases; however, no studies were performed yet to evaluate whether MTP plays a role in cancer. The MTP inhibitor lomitapide binds directly to MTP, thereby inhibiting the synthesis of triglyceride-rich VLDL in the liver. Therefore, the objective of this work was to study the effect of MTP inhibition on tumor growth. Adult male Balb/c nude mice were subjected to a xenograft model where Huh7 cells (5 x 106 per mouse) were injected subcutaneously into the right flank of mice. Four days post-cell inoculation, mice were randomly divided into two groups (8 mice/group). One group (Control) received the vehicle (methylcellulose, gastric probe), and the other group received 5 mg/kg bw/day lomitapide (gastric probe) for 15 days. Tumors were monitored using a caliper, and volumes were estimated based on the formula ?1/2 x length x width x height?. At the end of the treatment, mice were sacrificed, and tumors were excised and weighed. After treatment, lomitapide-treated mice showed higher tumor volume and weight (2-fold) than control mice. Plasma levels of triacylglycerol and cholesterol were decreased (−30%, and −40%, respectively) in lomitapide-treated mice compared to control mice. Tumor histology analysis showed no differences between groups on tissue architecture and fibrosis; however, lomitapide-treated mice presented with an accumulation of cytosolic lipid droplets. Then, we evaluated proliferation by immunoblotting in total tumor homogenates. We found lomitapide-treated mice presented with increased protein expression of proliferation cell nuclear antigen (PCNA) (+58%) compared to control mice. In line, positive Ki-67-stained nuclei were increased in tumor sections from lomitapide-treated mice. In conclusion, these studies represent the first steps in the evaluation of the role of MTP in cancer development and demonstrate that MTP may be participating in tumor growth.