کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1925781 | 1536415 | 2011 | 8 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Liver kinase B1 (LKB1) in the pathogenesis of UVB-induced murine basal cell carcinoma Liver kinase B1 (LKB1) in the pathogenesis of UVB-induced murine basal cell carcinoma](/preview/png/1925781.png)
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.
Research highlights
► LKB1 is a tumor suppressor.
► Contrary to most epithelial cancers where its expression is reduced, in skin neoplasm it is high.
► The activity of LKB1 is evidenced by its ability to enhance phosphorylation of AMPK.
► In BCCs enhanced LKB1 activity fails to block mTOR upregulation.
► LKB1 enhances pathogenesis of BCCs by augmenting beta catenin.
Journal: Archives of Biochemistry and Biophysics - Volume 508, Issue 2, 15 April 2011, Pages 204–211