title: Renal cell carcinoma escapes death by p53 depletion through transglutaminase 2-chaperoned autophagy.
abstract: In renal cell carcinoma, transglutaminase 2 (TGase 2) crosslinks p53 in autophagosomes, resulting in p53 depletion and the tumor's evasion of apoptosis. Inhibition of TGase 2 stabilizes p53 and induces tumor cells to enter apoptosis. This study explored the mechanism of TGase 2-dependent p53 degradation. We found that TGase 2 competes with human double minute 2 homolog (HDM2) for binding to p53; promotes autophagy-dependent p53 degradation in renal cell carcinoma (RCC) cell lines under starvation; and binds to p53 and p62 simultaneously without ubiquitin-dependent recognition of p62. The bound complex does not have crosslinking activity. A binding assay using a series of deletion mutants of p62, p53 and TGase 2 revealed that the PB1 (Phox and Bem1p-1) domain of p62 (residues 85-110) directly interacts with the β-barrel domains of TGase 2 (residues 592-687), whereas the HDM2-binding domain (transactivation domain, residues 15-26) of p53 interacts with the N terminus of TGase 2 (residues 1-139). In addition to the increase in p53 stability due to TGase 2 inhibition, the administration of a DNA-damaging anti-cancer drug such as doxorubicin-induced apoptosis in RCC cell lines and synergistically reduced tumor volume in a xenograft model. Combination therapy with a TGase 2 inhibitor and a DNA-damaging agent may represent an effective therapeutic approach for treating RCC.
authors.affiliation: Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea.
authors.forename: J-S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Republic of Korea.
authors.forename: D
authors.initials: D
authors.lastname: Hong
authors.affiliation: Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea.|Center for Innovative Drug Library Research, Dongguk University, Seoul, Korea.
authors.forename: N
authors.initials: N
authors.lastname: Kim
authors.affiliation: Institute of Life Science and Natural Resources, Korea University, Seoul, Republic of Korea.
authors.forename: W-K
authors.initials: WK
authors.lastname: Lee
authors.affiliation: Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea.
authors.forename: T-W
authors.initials: TW
authors.lastname: Sung
authors.affiliation: Center for Innovative Drug Library Research, Dongguk University, Seoul, Korea.
authors.forename: Y-D
authors.initials: YD
authors.lastname: Gong
authors.affiliation: Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Republic of Korea.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Kim
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C000588709:3-(phenylethynyl)-2-(2-(pyridin-2-yl)ethoxy)pyrido(3,2-b)pyrazine; D000903:Antibiotics, Antineoplastic; C118585:P62 protein, human; D011719:Pyrazines; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D002738:Chloroquine; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D019204:GTP-Binding Proteins