title: Liver kinase B1 (LKB1) in the pathogenesis of UVB-induced murine basal cell carcinoma.
abstract: LKB1, a known tumor suppressor, is mutated in Peutz-Jeghers Syndrome (PJS). It is responsible for the enhanced cancer risk in patients with PJS. Dysregulation of LKB1-dependent signaling also occurs in various epithelial cancers. UVB alters the expression of LKB1, though its role in the pathogenesis of skin cancer is unknown. Here we describe upregulation of LKB1 expression in UVB-induced murine basal cell carcinoma (BCC) and in human skin tumor keratinocytes. AMP-kinase and acetyl Co-A carboxylase, the downstream LKB1 targets, are also enhanced in this neoplasm. In addition, p-Akt, a kinase which inactivates GSK3β by its phosphorylation, is enhanced in BCCs. Consistently, an accumulation of p-GSK3β and an increase in activated nuclear β-catenin are found. mTOR signaling, which is also inhibited by LKB1, remains upregulated in BCCs. However, a marked decrease in the expression of sestrins, which function as potent negative regulators of mTOR is observed. Metformin, a known chemical inducer of this pathway, was found effective in immortalized HaCaT keratinocytes, but failed to activate the LKB1-dependent signaling in human carcinoma A431 cells. Thus, our data show that the LKB1/AMPK axis fails to regulate mTOR pathway, and a complex regulatory mechanism exists for the persistent mTOR activation in murine BCCs.
authors.affiliation: Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Yevgeniya A
authors.initials: YA
authors.lastname: Byekova
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Herrmann
authors.forename: Jianmin
authors.initials: J
authors.lastname: Xu
authors.forename: Craig A
authors.initials: CA
authors.lastname: Elmets
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
mesh_terms: D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D002280:Basal Cell Carcinoma / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D000072079:Patched Receptors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D051153:Wnt Proteins; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000263:Adenylate Kinase