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Anti-tumor effects of PIM1 inhibition in hepatocellular carcinoma

posted on 2020-08-24, 08:30 authored by Ming Sum Leung
Hepatocellular carcinoma (HCC) is the most common malignancy liver cancer. Targeted therapies are the new path for HCC treatment. Under hypoxic microenvironment, PIM1 (a serine/threonine kinase) is overexpressed in HCC. PIM1 induced tumor progression by regulating glycolysis. In this project, the efficacy of PIM1 inhibitor will be investigated in vitro and in vivo.

SGI-1776 and PIM447 were PIM1 inhibitors which were applied in this study. Both inhibitors were treated to HCC cell lines (MHCC97L and Huh7) under normoxic (20% O2) and hypoxic (1% O2) condition. The expression of PIM1 downstream targets was altered and which was confirmed by using western blotting. MTT assay was used to determine IC50 of PIM1 inhibitors in both HCC cell lines under normoxic and hypoxic conditions. The effect of PIM1 inhibitors on the proliferation and metastasis of HCC was estimated by cell proliferation, cell migration and invasion assays. To examine the effects of PIM1 inhibitors on the glucose uptake and chemosensitivity in HCC, glucose uptake assay and apoptosis assay with Annexin V/PI staining were applied respectively. A subcutaneous injection model using MHCC-97L cells and patient-derived tumor xenograft (PDTX) were applied to investigate the effect of PIM1 inhibitors on the in-vivo tumor growth by oral gavage treatment. To minimize the toxicity of PIM1 inhibitors, PIM1 inhibitors loaded PEGda gel was investigated in cell proliferation assay.

SGI-1776 and PIM447 treated HCC cells reduced the cell proliferation, migration and invasion in a dose-dependent manner under normoxic and hypoxic conditions. SGI-1776 and PIM447 treatment also sensitized HCC cells to cisplatin and doxorubicin under both conditions. Both PIM1 inhibitors suppressed PKM2 and glucose uptake in vitro. SGI-1776 and PIM447 treatment showed similar activities in HCC cells under normoxic and hypoxic condition. In vivo, tumor growth was inhibited upon administration of SGI-1776 and PIM447 in both MHCC-97L cell line and PDTX mouse model. PIM447 also sensitized cisplatin and doxorubicin in MHCC-97L cells bearing mice. PIM1 inhibitors loaded PEGda gel demonstrated a low releasing rate of PIM1 inhibitors in vitro. PEGda gel may apply in mouse model for minimizing the toxicity of PIM1 inhibitors.

PIM1 inhibitor showed the efficacy in suppressing HCC progression and glucose metabolism. It also improved chemosensitivity to HCC cells. PEGda gel helps to deliver PIM1 inhibitors to HCC. Therefore, PIM1 inhibitor can be regarded as a potential targeted therapy for HCC.


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