NEBL and AKT1 maybe new targets to eliminate the colorectal cancer cells resistance to oncolytic effect of vesicular stomatitis virus M-protein

Zoleikha Mamizadeh; Mohamad Reza Kalani; Masoud Parsania; Mohammad Mehdi Soltan Dallal; Abdolvahab Moradi

doi:10.1016/j.omto.2021.11.013

NEBL and AKT1 maybe new targets to eliminate the colorectal cancer cells resistance to oncolytic effect of vesicular stomatitis virus M-protein

Mol Ther Oncolytics. 2021 Nov 24:23:593-601. doi: 10.1016/j.omto.2021.11.013. eCollection 2021 Dec 17.

Authors

Zoleikha Mamizadeh¹, Mohamad Reza Kalani², Masoud Parsania³, Mohammad Mehdi Soltan Dallal⁴, Abdolvahab Moradi⁵

Affiliations

¹ Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
² Medical Cellular and Molecular Research Center, School of Advanced Medical Technologies, Golestan University of Medical Science, 1 Shastcola Avenue, Sari Road, Gorgan 49177-65181, Iran.
³ Department of Microbiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
⁴ Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
⁵ Department of Microbiology, School of Medicine, Golestan University of Medical Science, Golestan University of Medical Science, Gorgan, Iran.

Abstract

This study compares the oncolytic effect of vesicular stomatitis virus (VSV) wild type and M51R M-protein on the colorectal tumors of different invasive intensity on SW480 and HCT116 cell lines and 114 fresh colorectal cancer primary cell cultures. Fresh tumor samples were divided into two groups of lower stages (I/II) and higher stages (III/IV) regarding the medical records. The presence of two mutations in the PIK3CA gene and the expression of NEBL and AKT1 genes were evaluated. The cells were transfected with a plasmid encoding VSV wild-type and M51R mutant M-protein. Results showed either wild type or M51R mutant can kill SW480 and stage I/II primary cultures while mutant M-protein had no apoptotic effects on HCT116 cells and stage III/IV primary cultures. NEBL and AKT1 expression were significantly higher in resistant cells. Elevated caspase-9 activity confirmed that the intrinsic apoptosis pathway is the reason for cell death in lower-stage cells. Different tumors from the same cancer exhibit different treatment sensitivity due to genetic difference. NEBL and AKT1 gene expression may be responsible for this difference, which may be the target of future investigations. Therefore, tumor staging should be considered in oncolytic viral treatment as an interfering factor.

Keywords: VSV M-protein; colorectal cancer; oncolytic; resistance; tumor staging.