Intrinsic cellular signaling mechanisms determine the sensitivity of cancer cells to virus-induced apoptosis.

Yunfei Wang,Dawei Li,Jian Luo,Guimei Tian,Daiqing Liao,Lisa Y Zhao

doi:10.1038/srep37213

Abstract

Cancer cells of epithelial and mesenchymal phenotypes exhibit different sensitivities to apoptosis stimuli, but the mechanisms underlying this phenomenon remain partly understood. We constructed a novel recombinant adenovirus expressing Ad12 E1A (Ad-E1A12) that can strongly induce apoptosis. Ad-E1A12 infection of epithelial cancer cells displayed dramatic detachment and apoptosis, whereas cancer cells of mesenchymal phenotypes with metastatic propensity were markedly more resistant to this virus. Notably, forced detachment of epithelial cells did not further sensitize them to Ad-E1A12-induced apoptosis, suggesting that cell detachment is a consequence rather than the cause of Ad-E1A12-induced apoptosis. Ad-E1A12 increased phosphorylation of AKT1 and ribosomal protein S6 through independent mechanisms in different cell types. Ad-E1A12–induced AKT1 phosphorylation was PI3K-dependent in epithelial cancer cells, and mTOR-dependent in mesenchymal cancer cells. Epithelial cancer cells upon Ad-E1A12-induced detachment could not sustain AKT activation due to AKT1 degradation, but AKT1 activation was maintained in mesenchymal cancer cells. Expression of epithelial cell-restricted miR-200 family in mesenchymal cells limited mTOR signaling and sensitized them to Ad-E1A12-induced cell killing. Thus, epithelial cancer cells rely on the canonical PI3K-AKT signaling pathway for survival, while mesenchymal cancer cells deploy the PI3K-independent mTORC2-AKT axis in response to strong death stimuli.

Highlights

Epithelial cancer cells detached from native extracellular matrix (ECM) may survive after successfully undergoing epithelialmesenchymal transition (EMT) by engaging prosurvival factors through tumor cell-autonomous autocrine signaling or paracrine interactions within a specific microenvironment
In the breast cancer MDA-MB-468 cell line, Ad-E1A12 induced a high-level expression of the Ad5 E2A gene product DBP (DNA-binding protein) required for viral genome replication, the yield of the viral genome and the expression of capsids were significantly impaired compared to Ad5 (Fig. 1B and C)
This study presents evidence for the first time that distinct cell survival signaling mechanisms in epithelial and mesenchymal cancer cells seem to determine sensitivity to virus-induced apoptosis

Summary

Introduction

Epithelial cancer cells detached from native ECM may survive after successfully undergoing epithelialmesenchymal transition (EMT) by engaging prosurvival factors through tumor cell-autonomous autocrine signaling or paracrine interactions within a specific microenvironment. Breast cancer cells of mesenchymal phenotypes such as cells from the basal subtype generally express a low level of the miR-200 family[10,14]. Most TNBC cells are phenotypically mesenchymal-like, while cancer cells of the luminal subtypes, including the ERBB2-enriched subtype, have an epithelial appearance These subtypes show distinct gene mutational patterns[16]. The mutation of PIK3CA encoding the p110αcatalytic subunit of the class IA phosphatidylinositol 3-kinase (PI3K) has a much higher frequency in luminal subtypes (43%) compared to basal subtypes (7%), while the inverse is true for TP53 mutations with 84% cases of basal subtypes carrying TP53 mutations compared to 27% in luminal subtypes[16] These findings suggest that different breast cancer subtypes depend on distinct cellular signaling pathways for survival and sustained proliferation. Distinct cell survival signaling mechanisms appear to determine phenotypic outcomes in response to the strong apoptotic stimuli upon Ad-E1A12 infection

Methods

Results

Conclusion