Cancer 2013 July-5

 

TGF-β1 and hypoxia-dependent expression of MKP-1 leads tumor resistance to death receptor-mediated cell death.

Cell Death Dis. 2013 Feb 28;4:e521.

Junseong Park, Jungsul Lee, Wonseok Kang, Soyoung Chang, Eui-Cheol Shin, Chulhee Choi.

Department of Bio and Brain Engineering, Daejeon, Republic of Korea.

Abstract

Sporadic occurrence of transformed tumor cells is under the surveillance of the host immune system and such cells are effectively eliminated by immune-mediated cell death. During tumor progression, the antitumor effects of the tumor microenvironment are suppressed by diverse immunosuppressive mechanisms. In this research, we suggest novel immune evasion strategy of tumor cells through a transforming growth factor (TGF)-β1- and hypoxia-dependent mechanism. Experimental results showed that TGF-β1 and hypoxia induced mitogen-activated protein kinase phosphatase (MKP)-1 expression within 1 h, resulting in attenuation of c-Jun N-terminal kinase (JNK) phosphorylation and subsequent death receptor-mediated cell death. In addition, analysis of microarray data and immunostaining of MKP-1 in hepatocellular carcinoma (HCC) patient samples revealed that expression of MKP-1 is notably higher in tumors than in normal tissues, implying that MKP-1-dependent suppression of immune-mediated cell death takes place only in the tumor. To prove that MKP-1 can act as a mediator of immune escape by tumors, we determined whether chemo-resistance against several anticancer drugs could be overcome by knockdown of MKP-1. Cytotoxic assays showed that chemotherapy with siRNA targeting MKP-1 was significantly more effective than chemotherapy in the presence of MKP-1. Thus, we conclude that TGF-β1 and hypoxia ensure tumor cell survival and growth through expression of MKP-1.

PMID: 23449457

 

Interpretation

We demonstrated that MKP-1 (also known as DUSP-1) can act as a mediator of tumor cell resistance to immune surveillance and chemotherapy in HCC cells by selective suppression of JNK. Based on the experimental findings, we propose MKP-1-JNK as a regulatory intersection, and further investigated the tumor-specific nature of this control of cell death and its contribution to tumor resistance to the host immune system (as shown in Figure below). In accordance with functional importance of MKP-1 in cancer, we also evaluated MKP-1 as a novel drug target to overcome chemo-resistance to anti-cancer drugs. Because tumor cells exploit MKP-1 as a shield against immune-mediated cell death, our results provide a plausible mechanism by which tumor cells efficiently escape from immune-mediated cell death, and might provide a rational background for development of therapeutic interventions.

Junseong Park

Figure. Proposed model for MKP-1-JNK as a regulatory intersection responsible for tumor resistance to the host immune system

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