Tripeptidyl-peptidase II controls DNA damage responses and in vivo gamma-irradiation resistance of tumors.

Abstract

Cellular responses to gamma-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 gamma-irradiated cells. These events were dependent on mammalian target of rapamycin, a cytosolic/mitochondrial PIKK that is activated by gamma-irradiation. Lymphoma cells with inhibited expression of TPPII failed to efficiently stabilize p53 and had reduced ability to arrest proliferation in response to gamma-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 gamma-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.

• Authors: Xu Hong, Lu Lei, Brita Künert, Rajender Naredla, Steven E Applequist, Alf Grandien, Rickard Glas
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 15 Pg. 7165-74 (Aug 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17671184 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Enzyme Inhibitors
• RNA, Small Interfering
• Protein Serine-Threonine Kinases
• Aminopeptidases
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
• tripeptidyl-peptidase 2
• Serine Endopeptidases

Topics

• Amino Acid Sequence
• Aminopeptidases
• Animals
• DNA Damage (radiation effects)
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
• Enzyme Inhibitors (pharmacology)
• Flow Cytometry
• Gamma Rays
• Humans
• Immunoenzyme Techniques
• Lymphoma (enzymology, genetics, radiotherapy)
• Mice
• Mice, Inbred C57BL
• Molecular Sequence Data
• Phosphatidylinositol 3-Kinases (metabolism)
• Plasmids
• Protein Serine-Threonine Kinases (metabolism)
• RNA, Small Interfering (pharmacology)
• Radiation Tolerance
• Serine Endopeptidases (physiology)
• Signal Transduction (drug effects, radiation effects)
• Transfection
• Tumor Cells, Cultured (radiation effects)