Abstract
Tongue cancer resistance-related protein 1 (TCRP1) gene was first cloned from the multidrug resistance tongue cancer cell (Tca8113/pingyangmycin) in our lab. Our precious studies demonstrated that TCRP1 was involving in chemotherapy and radiotherapy resistance of tongue cancer cells, lung cancer cells and ovarian cancer cells. In this study, we showed that TCRP1 overexpression promotes cell transformation and tumorigenesis through hyperphosphorylation of the oncogenic kinase 3-phosphoinositide-dependent protein kinase-1 (PDK1) and AKT1, whereas inhibition of PDK1 by OSU-03012 or PDK1 small interfering RNA reversed TCRP1-mediated cell transformation. Importantly, TCRP1 was able to directly interact with PDK1, and 93–107 amino-acid and 109–124 amino-acid sites of TCRP1 were the common binding domain of PDK1. Moreover, in line with its oncogenic activity, we found that TCRP1 is often overexpressed in human in lung cancer, glioma, ovarian cancer, thyroid cancer, nasopharyngeal carcinoma, pancreatic cancer, stomach cancer and tongue carcinoma tissues. Spearman correlation analysis showed that the expression of TCRP1 has a positive correlation with p-PDK1, as well as p-AKT1 in lung cancer and gliomas tissues. Thus, TCRP1 may be a candidate as human oncoprotein that promotes cancer development by activation of PDK1/AKT1 signaling.
Highlights
Cancer is a complex and diverse set of diseases related to the unharnessed growth, enhanced survival and invasion of cells
PDK1 is known to be activated as a result of the accumulation of PIP3, and PTEN loss and PIK3CA activation both promote the accumulation of PIP3.11 we found that overexpression of Tongue cancer resistance-related protein 1 (TCRP1) did not affect the expression of phosphoinositide 3-kinase (PI3K), but modestly decreased PTEN expression (Figure 3a)
(c) NIH/3T3 cells were transfected with pEGFP-TCRP1/mut[1], or pEGFP-TCRP1/mut[2], total protein extracts were subjected to IP using TCRP1 antibody or control IgG, followed by WB with PDK1 antibody
Summary
Cancer is a complex and diverse set of diseases related to the unharnessed growth, enhanced survival and invasion of cells. Given the central role of PI3K/PDK1/Akt signaling as an oncogenic driver of tumorigenesis, more complete characterization of the interconnections between PI3K pathway components and different oncogenic pathways is necessary to identify underlying mechanisms of tumorigenesis that may be exploited therapeutically
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