The phytohormone forchlorfenuron decreases viability and proliferation of malignant mesothelioma cells in vitro and in vivo.

Walter Blum,Thomas Henzi,Christian G Bochet,László Pecze,Kim-Long Diep,Beat Schwaller

doi:10.18632/oncotarget.27341

Abstract

Malignant mesothelioma (MM) is one of the most aggressive cancer types with a patient’s life expectancy of typically less than one year upon diagnosis. The urgency of finding novel therapeutic approaches to treat mesothelioma is evident. Here we tested the effect of the plant-growth regulator forchlorfenuron (FCF), an inhibitor of septin function(s) in mammalian cells, on the viability and proliferation of MM cell lines, as well as other tumor cell lines derived from lung, prostate, colon, ovary, cervix and breast. Exposure to FCF strongly inhibited proliferation of human and mouse (most efficiently epithelioid) MM cells and all other tumor cells in a concentration-dependent manner and led to cell cycle arrest and cell death. The role of septin 7 (SEPT7), a presumably essential target of FCF in MM cells was confirmed by an shRNA strategy. FCF was robustly inhibiting tumor cell growth in vitro at low micromolar (IC50: ≈20-60µM) concentrations and more promisingly also in vivo. Initial experiments with FCF analogous revealed the importance of FCF’s chloride group for efficient cell growth inhibition. FCF’s rather low systemic toxicity might warrant for an extended search for other related and possibly more potent FCF analogues to target MM and putatively other septin-dependent tumors.

Highlights

Malignant mesothelioma (MM) is an extremely aggressive tumor arising from the pleural, peritoneal and pericardial mesothelial cell layer, in most cases after asbestos exposure [1]
We tested the effect of the plant-growth regulator forchlorfenuron (FCF), an inhibitor of septin function(s) in mammalian cells, on the viability and proliferation of MM cell lines, as well as other tumor cell lines derived from lung, prostate, colon, ovary, cervix and breast
Since FCF was initially dissolved in DMSO, cells grown in the presence of the same final DMSO concentration (≤0.5%) served as a negative control; MSTO-211H growth curves were essentially identical in the presence or absence of 0.5% DMSO

Summary

Introduction

Malignant mesothelioma (MM) is an extremely aggressive tumor arising from the pleural, peritoneal and pericardial mesothelial cell layer, in most cases after asbestos exposure [1]. Overexpression of septin 7 in MM cells decreases calretinin expression levels by septin’s binding to the calretinin (CALB2) promoter, acting as a negative transcriptional regulator. Calretinin overexpression reduces septin 7 levels indicative of a possibly reciprocal, antagonistic regulation; yet mechanistic details on the latter, i.e. calretinin decreasing septin 7 expression are currently unknown. Some septin family members (30-65 kDa) are expressed ubiquitously, while others show tissue-specific expression patterns. They are highly conserved, GTP-binding and membrane-interacting proteins and belong to the Ras-like GTPase superclass of phosphate-binding loop NTPases. Septin 7 expression in various glioma cell lines was found to be reduced compared to normal human glia cells, while overexpression suppressed glioma cell migration. Higher expression levels of septins 2/7 in breast cancer [14] and hepatocellular carcinomas (septin 7) hint towards a putative role as oncogenes in those cancer types [15]

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Results

Conclusion