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DNA Mismatch Repair Initiates 6-Thioguanine–Induced Autophagy through p53 Activation in Human Tumor Cells

Authors' Affiliation: Department of Radiation Oncology, Case Western Reserve University and the Case Integrative Cancer Biology Program, Case Comprehensive Cancer Center/University Hospitals of Cleveland, Cleveland, Ohio

Requests for reprints: Timothy J. Kinsella, Department of Radiation Oncology, LTR6068, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106-6068. Phone: 216-844-2530; Fax: 216-844-4799; E-mail: timothy.kinsella{at}uhhospitals.org.

Purpose: We investigate the roles of DNA mismatch repair (MMR) and p53 in mediating the induction of autophagy in human tumor cells after exposure to 6-thioguanine (6-TG), a chemotherapy drug recognized by MMR. We also examine how activation of autophagy affects apoptosis (type I cell death) after MMR processing of 6-TG.

Experimental Design: Using isogenic pairs of MLH1^–/MLH1⁺ human colorectal cancer cells (HCT116) and MSH2^–/MSH2⁺ human endometrial cancer cells (HEC59), we initially measure activation of autophagy for up to 3 days after 6-TG treatment using LC3, a specific marker of autophagy. We then assess the role of p53 in autophagic signaling of 6-TG MMR processing using both pifithrin- cotreatment to chemically inhibit p53 transcription and small hairpin RNA inhibition of p53 expression. Finally, we use Atg5 small hairpin RNA inhibition of autophagy to assess the effect on apoptosis after MMR processing of 6-TG.

Results: We find that MMR is required for mediating autophagy in response to 6-TG treatment in these human tumor cells. We also show that p53 plays an essential role in signaling from MMR to the autophagic pathway. Finally, our results indicate that 6-TG–induced autophagy inhibits apoptosis after MMR processing of 6-TG.

Conclusions: These data suggest a novel function of MMR in mediating autophagy after a chemical (6-TG) DNA mismatch damage through p53 activation. The resulting autophagy inhibits apoptosis after MMR processing of 6-TG.

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