PIM Kinase Inhibition Attenuates the Malignant Progression of Metastatic Hepatoblastoma

Janet R. Julson; Colin H. Quinn; Swatika Butey; Michael H. Erwin; Raoud Marayati; Nazia Nazam; Jerry E. Stewart; Elizabeth A. Beierle

doi:10.3390/ijms25010427

International Journal of Molecular Sciences (Dec 2023)

PIM Kinase Inhibition Attenuates the Malignant Progression of Metastatic Hepatoblastoma

Janet R. Julson,
Colin H. Quinn,
Swatika Butey,
Michael H. Erwin,
Raoud Marayati,
Nazia Nazam,
Jerry E. Stewart,
Elizabeth A. Beierle

Affiliations

Janet R. Julson: Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, 1600 7th Ave. South, Lowder Building, Suite 300, Birmingham, AL 35233, USA
Colin H. Quinn: Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, 1600 7th Ave. South, Lowder Building, Suite 300, Birmingham, AL 35233, USA
Swatika Butey: Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, 1600 7th Ave. South, Lowder Building, Suite 300, Birmingham, AL 35233, USA
Michael H. Erwin: Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, 1600 7th Ave. South, Lowder Building, Suite 300, Birmingham, AL 35233, USA
Raoud Marayati: Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, 1600 7th Ave. South, Lowder Building, Suite 300, Birmingham, AL 35233, USA
Nazia Nazam: Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, 1600 7th Ave. South, Lowder Building, Suite 300, Birmingham, AL 35233, USA
Jerry E. Stewart: Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, 1600 7th Ave. South, Lowder Building, Suite 300, Birmingham, AL 35233, USA
Elizabeth A. Beierle: Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, 1600 7th Ave. South, Lowder Building, Suite 300, Birmingham, AL 35233, USA

DOI: https://doi.org/10.3390/ijms25010427
Journal volume & issue: Vol. 25, no. 1
p. 427

Abstract

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Hepatoblastoma is the most common primary pediatric liver tumor. Children with pulmonary metastases at diagnosis experience survival rates as low as 25%. We have shown PIM kinases play a role in hepatoblastoma tumorigenesis. In this study, we assessed the role of PIM kinases in metastatic hepatoblastoma. We employed the metastatic hepatoblastoma cell line, HLM_2. PIM kinase inhibition was attained using PIM3 siRNA and the pan-PIM inhibitor, AZD1208. Effects of PIM inhibition on proliferation were evaluated via growth curve. Flow cytometry determined changes in cell cycle. AlamarBlue assay assessed effects of PIM kinase inhibition and cisplatin treatment on viability. The lethal dose 50% (LD50) of each drug and combination indices (CI) were calculated and isobolograms constructed to determine synergy. PIM kinase inhibition resulted in decreased HLM_2 proliferation, likely through cell cycle arrest mediated by p21. Combination therapy with AZD1208 and cisplatin resulted in synergy, potentially through downregulation of the ataxia-telangiectasia mutated (ATM) kinase DNA damage response pathway. When assessing the combined effects of pharmacologic PIM kinase inhibition with cisplatin on HLM_2 cells, we found the agents to be synergistic, potentially through inhibition of the ATM pathway. These findings support further exploration of PIM kinase inhibition as a therapeutic strategy for metastatic hepatoblastoma.

Published in International Journal of Molecular Sciences

ISSN: 1661-6596 (Print); 1422-0067 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Biology (General); Science: Chemistry
Website: http://www.mdpi.com/journal/ijms

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