TCRP1 promotes NIH/3T3 cell transformation by over-activating PDK1 and AKT1

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.

The lncRNA RMEL3 protects immortalized cells from serum withdrawal‐induced growth arrest and promotes melanoma cell proliferation and tumor growth

“…We reasoned that if RMEL3 plays a role in, or downstream of mitogen/survival factor‐stimulated signaling circuitries, under physiological conditions, its overexpression should bypass the necessity of mitogen stimulation for cell proliferation and survival. To test this hypothesis, we overexpressed RMEL3 in the immortalized, non‐transformed, and widely known NIH3T3 murine fibroblasts (Meloche & Pouysségur, ; Wang et al, ). We were surprised to find that, indeed, overexpression of RMEL3 bypassed the requirement of a mitogen/survival factor stimulation to support cell proliferation and survival.…”

TCRP1 induces tamoxifen resistance by promoting the activation of SGK1 in MCF‑7 cells

“…Previous studies reported that overexpressed TCRP1 promoted cell proliferation, cell growth, and cell cycle progression in NIH/3T3 cells. Moreover, upregulated TCRP1 promoted tumorigenesis of NIH/3T3 cells in nude mice (17). It has been reported that TCRP1-proficient cells exhibit an improved survival chance by increasing the levels of antiapoptotic proteins and decreasing the level of proapoptotic proteins (15).…”

“…Studies on the mechanisms of tamoxifen resistance demonstrated that tumor cells recruit various signaling pathways to develop drug resistance (28,29). It has been reported that TCRP1 promoted NIH/3T3 cell transformation by over-activating PDK1 and AKT1 (17). In addition, gene amplification or aberrant phosphorylation in the cytosol and nucleus may lead to aberrant PDK1 expression in human cancers such as in colon and breast cancer (30)(31)(32)(33).…”

“…Several studies have reported that TCRP1 mediates DDP-resistant lung cancer cells by inhibiting the degradation of Pol b (16). Moreover, TCRP1 plays an indispensable role in promoting the transformation of NIH/3T3 cells by overexpressing PDK1 and AKT1 (17). However, the effects of TCRP1 on MCF7-R cells and the underlying mechanism are still unknown.…”

Epigenetic silencing of miR-493 increases the resistance to cisplatin in lung cancer by targeting tongue cancer resistance-related protein 1(TCRP1)

“…3c ). Our previous reports indicated that TCRP1 might mediate the sensitivity to cisplatin via Akt signal pathway [ 16 , 21 , 22 ]. Here, we checked the activation status of Akt signal pathway.…”