Snail and Slug Mediate Radioresistance and Chemoresistance by Antagonizing p53-Mediated Apoptosis and Acquiring a Stem-Like Phenotype in Ovarian Cancer Cells

Abstract

The transcriptional repressors Snail and Slug contribute to cancer progression by mediating epithelial-mesenchymal transition (EMT), which results in tumor cell invasion and metastases. We extend this current understanding to demonstrate their involvement in the development of resistance to radiation and paclitaxel. The process is orchestrated through the acquisition of a novel subset of gene targets that is repressed under conditions of stress, effectively inactivating p53-mediated apoptosis, while another subset of targets continues to mediate EMT. Repressive activities are complemented by a concurrent derepression of specific genes resulting in the acquisition of stem celllike characteristics. Such cells are bestowed with three critical capabilities, namely EMT, resistance to p53-mediated apoptosis, and a self-renewal program, that together define the functionality and survival of metastatic cancer stem cells. EMT provides a mechanism of escape to a new, less adverse niche; resistance to apoptosis ensures cell survival in conditions of stress in the primary tumor; whereas acquisition of ''stemness'' ensures generation of the critical tumor mass required for progression of micrometastases to macrometastases. Our findings, besides achieving considerable expansion of the inventory of direct genes targets, more importantly demonstrate that such elegant cooperative modulation of gene regulation mediated by Snail and Slug is critical for a cancer cell to acquire stem cell characteristics toward resisting radiotherapy-or chemotherapy-mediated cellular stress, and this may be a determinative aspect of aggressive cancer metastases.

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

“…44 Furthermore, besides their role in E-cadherin repression, 45,46 Slug and Snail have been implicated in radioresistance-associated EMT. 47,48 Snail enhances resistance to apoptosis by activating the PI3K/Akt and Erk1/2 pathways, 28 consistent with our data showing increased radiosensitivity after inhibition of PI3K/Atk and Erk1/2 and downregulation of Snail. Notably, Snail is a substrate of the major radiation-induced kinase ATM, and this phosphorylation is involved in radiosensitivity.…”

“…The radiationinduced phenotypic heterogeneity, we report, might reflect transient cellular plasticity as well as stress-evoked responses of preexistent subsets cells seen in the parental DU145 and PC-3 cell populations. [40][41][42][43][44][45][46][47][48][49][50][51][52] Ionizing radiation can promote traits of EMT in normal human mammary epithelium, 41 lung carcinoma 42,43 and colorectal cancer cells. 44 Furthermore, besides their role in E-cadherin repression, 45,46 Slug and Snail have been implicated in radioresistance-associated EMT.…”

Critical role for transcriptional repressor Snail2 in transformation by oncogenic RAS in colorectal carcinoma cells

“…In addition to causing loss of viability in RAS mutant mesenchymal cells, Snail2 knockdown increases the sensitivity of these cells to cytotoxic drugs. Snail2 inhibition has previously been shown to sensitize cells to DNA-damaging agents, in part by directing the p53 response away from apoptosis (Inoue et al, 2002;Perez-Losada et al, 2003;Kajita et al, 2004;Wu et al, 2005;Vannini et al, 2007;Vitali et al, 2008;Kurrey et al, 2009). Although the function of Snail2 as a transcriptional regulator does not make it an attractive target for pharmacological targeting, the data presented here suggest that its inhibition could be a good way of targeting some of the most intractable tumour types, those with a mutant RAS oncogene and a mesenchymal phenotype.…”

Mechanism of the Mesenchymal–Epithelial Transition and Its Relationship with Metastatic Tumor Formation

“…In support of the relationship between therapy resistance and EMT, it was found that endometrial carcinoma cells with resistance to radiotherapy exhibit a mesenchymal phenotype, including decreased expression of E-cadherin (128). Upregulation of Snail and Slug in ovarian cancer cells is also associated with acquisition of radioresistance and chemoresistance of ovarian cancer cells (107). Furthermore, the EMT process has been proposed to be associated with resistance to targeted therapy (127,129,130), potentially bypassing the dependence on this pathway by activation of its downstream targets (131).…”