Pharmacological inhibition of PIM1 suppresses tumor progression and enhances chemosensitivity in hepatocellular carcinoma

Abstract

Background and aims: Hepatocellular carcinoma (HCC) is a common and aggressive malignancy worldwide. Targeted therapies provide new strategic treatment options for HCC. PIM1, a serine/threonine kinase, is upregulated in the hypoxic microenvironment of HCC and promotes tumor progression through regulating glycolysis. In the current study, we will evaluate the preclinical efficacy of targeting PIM1 by specific inhibitor in vitro and in vivo. Method: PIM kinase inhibitor 1SGI-1776 was used to treat HCC cell lines including MHCC97L and Huh7. Altered expression of downstream targets of PIM 1 was confirmed by western blotting. IC50 was determined by MTTassay. Cell proliferation, cell motility and matrigel invasion assays were employed to study the effects of proliferation and metastasis upon altered PIM1 functions. Glucose uptake assay and apoptosis assay with Annexin V/PI staining were carried out to examine the effects of glucose uptake and chemosensitivity, respectively. In vivo tumor growth was investigated by a subcutaneous injection model using MHCC97L cells coupled with inhibitor treatment by oral lavage. Results: Treatment of HCC cells with SGI-1776 resulted in a concentration-dependent reduction in cell proliferation, migration and invasion. SGI-1776 treatment also sensitized HCC cells to cisplatin and suppressed PKM2 and glucose uptake in vitro. In vivo tumor growth was suppressed upon administration of SGI-1776. Conclusion: Targeting PIM1 by PIM inhibitor demonstrates efficacy in suppressing HCC progression, hampering glucose metabolism, and enhancing chemosensitivity of HCC cells. It is a potential targeted therapy for HCC.