Research Papers:

Inactivation of p38 MAPK contributes to stem cell-like properties of non-small cell lung cancer

Yan Fang, Juan Wang, Guanwen Wang, Chen Zhou, Peng Wang, Shuangtao Zhao, Shaorong Zhao, Shan Huang, Weijun Su, Pengling Jiang, Antao Chang, Rong Xiang and Peiqing Sun _

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Oncotarget. 2017; 8:26702-26717. https://doi.org/10.18632/oncotarget.15804

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Yan Fang1, Juan Wang1, Guanwen Wang1, Chen Zhou1, Peng Wang1, Shuangtao Zhao1, Shaorong Zhao1, Shan Huang2, Weijun Su1,2, Pengling Jiang3, Antao Chang1,2, Rong Xiang1, Peiqing Sun1,2

1Department of Immunology, School of Medicine, Nankai University, Tianjin, China

2Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest University Medical Center, Winston-Salem, North Carolina, USA

3Key Laboratory of Cancer and Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China

Correspondence to:

Peiqing Sun, email: [email protected]

Rong Xiang, email: [email protected]

Keywords: p38, Hsp27, MK2, stemness markers, lung cancer stem cells

Received: November 15, 2016     Accepted: February 15, 2017     Published: March 01, 2017


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.

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