ATM-mediated PTEN phosphorylation promotes PTEN nuclear translocation and autophagy in response to DNA-damaging agents in cancer cells

• Published in: Autophagy Vol. 11; no. 2; pp. 239 - 252
• Main Authors: Chen, Jing-Hong, Zhang, Peng, Chen, Wen-Dan, Li, Dan-Dan, Wu, Xiao-Qi, Deng, Rong, Jiao, Lin, Li, Xuan, Ji, Jiao, Feng, Gong-Kan, Zeng, Yi-Xin, Jiang, Jian-Wei, Zhu, Xiao-Feng
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.02.2015
• Subjects: Active Transport, Cell Nucleus - drug effects; AKT/PKB, v-akt murine thymoma viral oncogene homolog; AMPK, protein kinase, AMP-activated; Antineoplastic Agents - pharmacology; Ataxia Telangiectasia Mutated Proteins - metabolism; ATG, autophagy-related; ATM; ATM, ATM serine/threonine kinase; autophagy; Autophagy - drug effects; Autophagy - physiology; Baf.A; bafilomycin A; Basic Science Research Papers; CASP3, caspase 3, apoptosis-related cysteine peptidase; CCND1, cyclin D1; CDDP, cisplatin; CENPC/CENP-C, centromere protein C; Cisplatin - pharmacology; CITED1/p300/CBP, Cbp/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 1; CSNK2/CK2, casein kinase 2; DNA Damage; DSBs, DNA double-strand breaks; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; GLTSCR2/PICT-1, glioma tumor suppressor candidate region gene 2; GSK3B, glycogen synthase kinase 3 β; GST, glutathione S-transferase; H2A histone family; H2AFX; Humans; JUN; jun proto-oncogene; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; member X; MTORC1, mechanistic target of rapamycin complex 1; MVP, major vault protein; NC, normal control; NEDD4, neural precursor cell expressed, developmentally down-regulated 4, E3 ubiquitin protein ligase; PAGE, polyacrylamide gel electrophoresis; PARP, poly (ADP-ribose) polymerase 1; phosphatidylinositol (3, 4, 5)-trisphosphate; Phosphorylation - drug effects; PI3K, phosphoinositide 3-kinase; PMSF, phenylmethanesulfonyl fluoride; PPase, protein phosphatase; PtdIns(3, 4, 5)P; PTEN; PTEN Phosphohydrolase - metabolism; PTEN, phosphatase and tensin homolog; RAD51, RAD51 recombinase; ribosomal protein S6 kinase, 70kDa; RPS6KB/p70S6K; SDS, sodium dodecyl sulfate; SESN2, sestrin 2; Signal Transduction - drug effects; Signal Transduction - genetics; siRNA, small interfering RNA; SQSTM1/p62, sequestosome 1; Topoisomerase I Inhibitors - pharmacology; topotecan; Topotecan - pharmacology; TP53, tumor protein p53; TPT, topotecan; TUBA4A, tubulin, α, 4a; Tumor Suppressor Proteins - metabolism; WT, wild type; YFP, yellow fluorescent protein; SESN2, sestrin 2; CASP3, caspase 3, apoptosis-related cysteine peptidase; PPase, protein phosphatase; YFP, yellow fluorescent protein; PTEN; ATG, autophagy-related; CITED1/p300/CBP, Cbp/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 1; member X; RAD51, RAD51 recombinase; topotecan; TPT, topotecan; DSBs, DNA double-strand breaks; autophagy; GST, glutathione S-transferase; TUBA4A, tubulin, α, 4a; PtdIns(3, 4, 5)P3, phosphatidylinositol (3, 4, 5)-trisphosphate; H2AFX; MVP, major vault protein; TP53, tumor protein p53; NEDD4, neural precursor cell expressed, developmentally down-regulated 4, E3 ubiquitin protein ligase; CCND1, cyclin D1; ATM, ATM serine/threonine kinase; Baf.A1, bafilomycin A1; AKT/PKB, v-akt murine thymoma viral oncogene homolog; CDDP, cisplatin; NC, normal control; PMSF, phenylmethanesulfonyl fluoride; PI3K, phosphoinositide 3-kinase; DNA damage; PARP, poly (ADP-ribose) polymerase 1; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; SDS, sodium dodecyl sulfate; H2A histone family; GLTSCR2/PICT-1, glioma tumor suppressor candidate region gene 2; MTORC1, mechanistic target of rapamycin complex 1; PAGE, polyacrylamide gel electrophoresis; CENPC/CENP-C, centromere protein C; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; AMPK, protein kinase, AMP-activated; GFP, green fluorescent protein; JUN; SQSTM1/p62, sequestosome 1; WT, wild type; ribosomal protein S6 kinase, 70kDa; RPS6KB/p70S6K; siRNA, small interfering RNA; CSNK2/CK2, casein kinase 2; GSK3B, glycogen synthase kinase 3 β; ATM; jun proto-oncogene; PTEN, phosphatase and tensin homolog
• ISSN: 1554-8627; 1554-8635; 1554-8635
• DOI: 10.1080/15548627.2015.1009767

PTEN (phosphatase and tensin homolog), a tumor suppressor frequently mutated in human cancer, has various cytoplasmic and nuclear functions. PTEN translocates to the nucleus from the cytoplasm in response to oxidative stress. However, the mechanism and function of the translocation are not completely understood. In this study, topotecan (TPT), a topoisomerase I inhibitor, and cisplatin (CDDP) were employed to induce DNA damage. The results indicate that TPT or CDDP activates ATM (ATM serine/threonine kinase), which phosphorylates PTEN at serine 113 and further regulates PTEN nuclear translocation in A549 and HeLa cells. After nuclear translocation, PTEN induces autophagy, in association with the activation of the p-JUN-SESN2/AMPK pathway, in response to TPT. These results identify PTEN phosphorylation by ATM as essential for PTEN nuclear translocation and the subsequent induction of autophagy in response to DNA damage.