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Control of Multidrug Resistance Gene mdr1 and Cancer Resistance to Chemotherapy by the Longevity Gene sirt1

¹ Departments of Pediatrics, ² Pathology, and ³ Molecular Pharmacology and Biological Chemistry, Children's Memorial Research Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

Requests for reprints: Abdelhadi Rebbaa, Department of Pediatrics, Children's Memorial Research Center, Northwestern University, 2430 North Halsted, M/C 224 Chicago, IL 60614. Phone: 773-755-6532; Fax: 773-755-6523; E-mail: arebbaa{at}childrensmemorial.org.

Irreversible growth arrest (also called senescence) has emerged recently as a tumor suppressor mechanism and a key determinant of cancer chemotherapy outcome. Previous work from our laboratory suggested that the cellular ability to undergo or to escape senescence dictates its fate to become drug-sensitive or drug-resistant, respectively. In the present study, we made the hypothesis that longevity genes, by virtue of their ability to inhibit senescence, may contribute to the onset of drug resistance. We report that expression of the longevity gene sirt1 increased both at the RNA and protein levels in all the five drug-resistant cell lines tested when compared with their drug-sensitive counterparts. In addition, biopsies from cancer patients treated with chemotherapeutic agents also expressed high levels of this molecule. These changes were specific for sirt1 because the expression of other members of its family was not affected. More importantly, small interfering RNA–mediated down-regulation of sirt1 significantly reversed the resistance phenotype and reduced expression of the multidrug resistance molecule P-glycoprotein. This was further confirmed by ectopic overexpression of sirt1, which induced expression of P-glycoprotein and rendered cells resistant to doxorubicin. Collectively, these findings uncovered a novel function for the longevity gene sirt1 as a potential target for diagnosis and/or treatment of cancer resistance to chemotherapy. They also describe a proof of principle that signaling pathways implicated in longevity may share similarities with those leading to development of drug resistance in cancer.

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