Sestrin2 protein positively regulates AKT enzyme signaling and survival in human squamous cell carcinoma and melanoma cells.
Skin cancer is the most common cancer in the United States and is mainly caused by environmental UV radiation. Reducing skin cancer incidence is becoming an urgent issue. The stress-inducible protein Sestrin2 (Sesn2) plays an important role in maintaining redox and metabolic homeostasis and their related pathologies. However, the role of Sesn2 in cancer remains unclear. Here we show that UVB radiation induces Sesn2 expression in normal human keratinocytes, mouse skin, normal human melanocytes, and melanoma cells. In addition, Sesn2 promotes AKT activation through a PTEN-dependent mechanism. Sesn2 deletion or knockdown sensitizes squamous cell carcinoma (SCC) cells to 5-fluorouracil-induced apoptosis and melanoma cells to UVB- and vemurafenib-induced apoptosis. In mice Sesn2 knockdown suppresses tumor growth from injected human SCC and melanoma cells. Last, as compared with normal skin, Sesn2 is up-regulated in both human skin SCC and melanoma. Our findings demonstrate that Sesn2 promotes AKT activation and survival in response to UVB stress and chemotherapeutics and suggest that Sesn2 is oncogenic in skin SCC and melanoma.
From the Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Illinois 60637.
Baozhong
B
Zhao
From the Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Illinois 60637.
Palak
P
Shah
Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298.
Andrei V
AV
Budanov
From the Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Illinois 60637.
Lei
L
Qiang
From the Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Illinois 60637.
Mei
M
Ming
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Andrew
A
Aplin
From the Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Illinois 60637.
Diane M
DM
Sims
From the Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Illinois 60637, yyhe@medicine.bsd.uchicago.edu.
Yu-Ying
YY
He
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002470:Cell Survival; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D047368:Tumor Burden; D015854:Up-Regulation; D000084622:Sestrins
D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D051057:Proto-Oncogene Proteins c-akt; C465398:SESN2 protein, human; D000084622:Sestrins
Akt PKB; Apoptosis; Cancer; Cancer Biology; Tumor