Abstract
Cancer stem cells (CSCs) are recognized as the major source for cancer initiation and recurrence. Yet, the mechanism by which the cancer stem cell properties are acquired and maintained in a cancer cell population is not well understood. In the current study, we observed that the level of active p38 MAPK is downregulated, while the level of the stemness marker SOX2 is upregulated in lung cancer tissues as compared to normal tissues. We further demonstrated that inactivation of p38 is a potential mechanism contributing to acquisition and maintenance of cancer stem cell properties in non-small cell lung cancer (NSCLC) cells. p38, in particular the p38γ and p38δ isoforms, suppresses the cancer stem cell properties and tumor initiating ability of NSCLC cells by promoting the ubiquitylation and degradation of stemness proteins such as SOX2, Oct4, Nanog, Klf4 and c-Myc, through MK2-mediated phosphorylation of Hsp27 that is an essential component of the proteasomal degradation machinery. In contrast, inactivation of p38 in lung cancer cells leads to upregulation of the stemness proteins, thus promoting the cancer stem cell properties of these cells. These findings have demonstrated a novel mechanism by which cancer stem cell properties are acquired and maintained in a cancer cell population, and have revealed a new function of the p38 pathway in suppressing cancer development. These studies have also identified a new pathway that can potentially serve as a target for cancer therapies aimed at eliminating CSCs.
Highlights
Lung cancer is one of the major causes of cancerdeath in the world [1]
We further demonstrated that inactivation of p38 is a potential mechanism contributing to acquisition and maintenance of cancer stem cell properties in non-small cell lung cancer (NSCLC) cells. p38, in particular the p38γ and p38δ isoforms, suppresses the cancer stem cell properties and tumor initiating ability of NSCLC cells by promoting the ubiquitylation and degradation of stemness proteins such as SOX2, Oct4, Nanog, Klf4 and c-Myc, through MK2-mediated phosphorylation of Hsp27 that is an essential component of the proteasomal degradation machinery
We perform the Spearman's rank correlation test, and found a weak negative correlation between SOX2 levels and p-p38 levels, with a p value of 0.128. These observations raise a possibility that active p38 may inhibit the expression of stemness proteins such as SOX2, and that inactivation of p38 in lung cancer cells leads to increased expression of SOX2, promoting the acquisition of cancer stem cell-like properties
Summary
Lung cancer is one of the major causes of cancerdeath in the world [1]. Lung cancer can be classified into small cell lung carcinoma and non-small cell lung carcinoma (NSCLC) [2]. Cancer stem cells (CSCs) are a small population of cancer cells that possess capabilities of self-renewal, differentiation, and tumor initiation in vivo [4]. Overexpression of Oct (Octamer-binding transcription factor 4), SOX2 (SRY (sex determining region Y)-box 2), Nanog, Klf (Kruppel-like factor 4) and c-Myc, can induce somatic cells to acquire pluripotency [5]. These proteins serve as the CSCs markers [6,7,8]. The mechanisms by which SOX2 and other CSC markers are overexpressed in cancer are unknown It remains unclear how CSCs are acquired and how the stemness is maintained in a cancer cell population
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