Inhibition of microsomal triacylglyceride transfer protein (MTP) by lomitapide favors tumor growth in mice

COMANZO, CARLA G.; VERA, MARINA C.; LUCCI ALVARO; HEIT BARBINI FJ; LORENZETTI, FLORENCIA; FERRETTI, ANABELA C.; CEBALLOS, MARÍA PAULA; CARRILLO, MARÍA CRISTINA; ALVAREZ, MARÍA DE LUJÁN; QUIROGA, ARIEL D.

Congreso; LXVI Reunión Científica Anual de SAIC; 2021

Microsomal triacylglycerol transfer protein (MTP) locates in the lumenof the endoplasmic reticulum and participates in the secretionof lipids from the liver as very low-density lipoproteins (VLDL). TheMTP inhibitor lomitapide binds directly to MTP inhibiting the synthesisof VLDL in the liver. The objective of this work was to study theeffect of MTP inhibition on tumor growth. Adult male Balb/c nudemice were subjected to a xenograft model where Huh7 cells (5x106/mouse) were injected subcutaneously into the right flank of mice. After4 days, mice were divided into 2 groups. Control group receivedvehicle (methylcellulose, gavage) and another group received 5 mg/kg bw/day lomitapide (gavage) for 15 days. Tumors were monitoredusing a caliper and volumes were estimated based on the formula?1/2 x l x w x h?. At the end, mice were sacrificed, and tumors excisedand weighed. Lomitapide-treated mice showed higher tumor volumeand weight (2-fold) than control mice. Plasma levels of triacylglyceroland cholesterol were decreased (-30%, and -40%, respectively)in lomitapide-treated mice compared to control mice. Tumor histologyshowed no differences between groups on tissue architecture;however, lomitapide-treated mice presented with accumulation ofcytosolic lipid droplets. Analysis of proliferation by immunoblottingin total tumor homogenates showed that lomitapide-treated micepresented with increased expression of proliferation cell nuclearantigen (PCNA) (+58%). In line, positive Ki-67-stained nuclei wereincreased in tumor sections from lomitapide-treated mice. Conclusion:these studies demonstrate that MTP inhibition, blocking lipidsecretion from the liver, could lead to increased tumor growth, andrepresent the first steps in the evaluation of the role of MTP in cancerdevelopment.