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J. Biol. Chem., Vol. 279, Issue 45, 46706-46714, November 5, 2004

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Induction of Stem Cell Factor/c-Kit/Slug Signal Transduction in Multidrug-resistant Malignant Mesothelioma Cells^*

Alfonso Catalano¶, Sabrina Rodilossi, Maria Rita Rippo, Paola Caprari||, and Antonio Procopio

From the Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona 60131, Italy, the Laboratory of Cytology, Italian National Research Centers on Aging, Ancona 60124, Italy, and the ^||Neural Development Group, Mouse Cancer Genetics Program, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21701

Malignant mesothelioma (MM) is strongly resistant to conventional chemotherapy by unclear mechanisms. We and others have previously reported that cytokine- and growth factor-mediated signal transduction is involved in the growth and progression of MM. Here, we identified a pathway that involves stem cell factor (SCF)/c-Kit/Slug in mediating multidrug resistance of MM cells. When we compared gene expression profiles between five MM cells and their multidrug-resistant (MM DX) sublines, we found that MM DX cells expressed both SCF and c-Kit and had higher mRNA levels of Slug. Knockdown of c-Kit or Slug expression with their respective small interfering RNA sensitized MM DX cells to the induction of apoptosis by different chemotherapeutic agents, including doxorubicin, paclitaxel, and vincristine. Transfection of c-Kit in parental MM cells in the presence of SCF up-regulated Slug and increased resistance to the chemotherapeutic agents. Moreover, MM cells expressing Slug showed a similar increased resistance to the chemotherapeutic agents. These results indicate that induction of Slug by autocrine production of SCF and c-Kit activation plays a key role in conferring a broad spectrum chemoresistance on MM cells and reveal a novel signal transduction pathway for pharmacological or genetic intervention of MM patients.

Received for publication, June 16, 2004 , and in revised form, August 23, 2004.

^* This work was supported by grants from the Italian Ministry of Research and from Associazione Italiana per la Ricerca contro il Cancro (to A. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by a fellowship from Fondazione Italiana per la Ricerca contro il Cancro. To whom correspondence should be addressed: Dept. of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Via Ranieri, Ancona 60131, Italy. Tel.: 39-0712204623; Fax: 39-0712204618; E-mail: catgfp{at}yahoo.it.

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