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Tripeptidyl-peptidase II Controls DNA Damage Responses and In vivo -Irradiation Resistance of Tumors

¹ Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital-Huddinge; and ² Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

Requests for reprints: Rickard Glas, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital-Huddinge, S-171 76 Stockholm, Sweden. Phone: 46-8-5177-9897; Fax: 46-8-313147; E-mail: rickard.glas{at}ki.se.

Cellular responses to -irradiation exposure are controlled by phosphatidylinositol 3-kinase–related kinases (PIKK) in the nucleus, and in addition, cytosolic PIKKs may have a role in such responses. Here, we show that the expression of tripeptidyl-peptidase II (TPPII), a high molecular weight cytosolic peptidase, required PIKK signaling and that TPPII was rapidly translocated into the nucleus of -irradiated cells. These events were dependent on mammalian target of rapamycin, a cytosolic/mitochondrial PIKK that is activated by -irradiation. Lymphoma cells with inhibited expression of TPPII failed to efficiently stabilize p53 and had reduced ability to arrest proliferation in response to -irradiation. We observed that TPPII contains a BRCA COOH-terminal–like motif, contained within sequences of several proteins involved in DNA damage signaling pathways, and this motif was important for nuclear translocation of TPPII and stabilization of p53. Novel tripeptide-based inhibitors of TPPII caused complete in vivo tumor regression in mice in response to relatively low doses of -irradiation (3–4 Gy/wk). This was observed with established mouse and human tumors of diverse tissue backgrounds, with no tumor regrowth after cancellation of treatment. These TPPII inhibitors had minor effects on tumor growth as single agent and had low cellular toxicity. Our data indicated that TPPII connects signaling by cytosolic/mitochondrial and nuclear PIKK-dependent pathways and that TPPII can be targeted for inhibition of tumor therapy resistance. [Cancer Res 2007;67(15):7165–74]