Colorectal carcinoma cells—Regulation of survival and growth by SGK1

Läng, Florian; Perrotti, Nicola; Stournaras, Christos

doi:10.1016/j.biocel.2010.05.016

Cited by 80 publications

(99 citation statements)

References 34 publications

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“…In addition, overexpression of beta-catenin and β-catenin/Wnt signaling is associated with many cancers including colorectal carcinomas [13,16,20,21]. Accordingly, we tested whether mAR activation alters beta-catenin gene expression.…”

Section: Resultsmentioning

confidence: 99%

Membrane Androgen Receptor Down-Regulates c-Src-Activity and Beta-Catenin Transcription and Triggers GSK-3beta-Phosphorylation in Colon Tumor Cells

Honisch

Kounenidakis

et al. 2014

Cell Physiol Biochem

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Background/Aims: Functional membrane androgen receptors (mARs) have recently been described in colon tumor cells and tissues. Their activation by specific testosterone albumin conjugates (TAC) down-regulates the PI-3K/Akt pro-survival signaling and triggers potent pro-apoptotic responses both, in vitro and in vivo. The present study explored the mAR-induced regulation of gene products implicated in the tumorigenic activity of Caco2 colon cancer cells. Methods: In Caco2 human colon cancer cells transcript levels were determined by RT-PCR, protein abundance and phosphorylation by Western blotting and confocal microscopy, as well as cytoskeletal architecture by confocal microscopy. Results: We report time dependent significant decrease in Tyr-416 phosphorylation of c-Src upon mAR activation. In line with the reported late down-regulation of the PI-3K/Akt pathway in testosterone-treated colon tumors, GSK-3beta was phosphorylated at Tyr-216 after long term stimulation of the cells with TAC, a finding supporting the role of this kinase to promote apoptosis. PCR analysis revealed significant decrease of beta-catenin and cyclin D1 transcript levels following TAC treatment. Moreover, confocal laser scanning microscopic analysis disclosed co-localization of beta-catenin with actin cytoskeleton. It is thus conceivable that beta-catenin may participate in the reported modulation of cytoskeletal dynamics in mAR stimulated Caco2 cells. Conclusions: Our results provide strong evidence that mAR activation regulates late expression and/or activity of the tumorigenic gene products c-Src, GSK-3beta, and beta-catenin thus facilitating the pro-apoptotic response in colon tumor cells.

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Section: Resultsmentioning

confidence: 99%

Membrane Androgen Receptor Down-Regulates c-Src-Activity and Beta-Catenin Transcription and Triggers GSK-3beta-Phosphorylation in Colon Tumor Cells

Honisch

Kounenidakis

et al. 2014

Cell Physiol Biochem

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“…As SGK1 is stimulated by growth factors (40,41), the kinase links growth factor receptor-mediated signaling with the store-operated Ca 2ϩ entry. Orai1 (42)(43)(44)(45) and SGK1 (46,47) have been shown to be critically important in the regulation of cell proliferation. SOCE has further been shown to participate in cytokine production (48), migration of tumor (49), and mast cells (50).…”

Section: Discussionmentioning

confidence: 99%

Transcription Factor NF-κB Regulates Expression of Pore-forming Ca2+ Channel Unit, Orai1, and Its Activator, STIM1, to Control Ca2+ Entry and Affect Cellular Functions

Eylenstein

Schmidt

et al. 2012

Journal of Biological Chemistry

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Alterations of cytosolic Ca 2ϩ activity participate in the regulation of a wide variety of cellular functions including excitation-contraction coupling, exocytosis, migration, cell proliferation, and cell death (1-4). Cytosolic Ca 2ϩ is increased by release of Ca 2ϩ from intracellular stores and/or Ca 2ϩ entry across the cell membrane (5). Ca 2ϩ release from intracellular stores results in the stimulation of Ca 2ϩ release-activated Ca 2ϩ channel (CRAC) 2 (6, 7), which consists of the pore forming units Orai1, -2, and/or -3 (8 -10) and the endoplasmic reticulum-located regulatory subunit STIM1 or -2 (11-13). The stimulation of the channel leads to the inward current I CRAC and the store-operated Ca 2ϩ entry (SOCE). Recent observations uncovered the powerful stimulation of I CRAC and SOCE by the serum and glucocorticoid-inducible kinase SGK1 (14), a kinase stimulated by growth factors and involved in stress response (15) and regulation of cell survival (16). SGK1 is partially effective through phosphorylation of the ubiquitin ligase Nedd4-2 (neuronal precursor cells expressed developmentally down-regulated). Nedd4-2 ubiquitinates Orai1, thus preparing the channel protein for degradation (14). The effect of Nedd4-2 on Orai1 parallels that of Nedd4-2 on the epithelial Na ϩ channel ENaC (16, 17). The phosphorylation of Nedd4-2 leads to binding of the ubiquitin ligase to the protein 14-3-3, which prevents the interaction with the channel protein (18). Accordingly, SGK1 enhances Orai1 protein abundance in the cell membrane (14). STIM is similarly regulated by ubiquitination (19). However, the effect of SGK1 on Orai1 protein abundance is only in part explained by Nedd4-2-dependent protein degradation. Therefore, further experiments were performed to explore whether SGK1, in addition, stimulates Orai1 and/or STIM1 expression. As a matter of fact, RT-PCR revealed an increase of Orai1 and STIM1 transcript levels after expression of constitutively active SGK1. Thus, further experiments were performed to uncover the transcription factor involved. Previously, SGK1 has been shown to foster nuclear translocation and activation of nuclear factor B (NF-B) (20 -22). Accordingly, this study explored the putative involvement of NF-B subunits p65 (RELA), p50 (NFKB1), and p52 (NFKB2) in the regulation of Orai1 and STIM1 expression. EXPERIMENTAL PROCEDURES

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“…Taken together, these observations suggest an important role for Sgk1 in carcinogenesis and in the mechanisms responsible for resistance to chemotherapy [23]. Sgk1 may thus be considered an interesting molecular target in the therapy of some human tumors [24; 15,25].…”

Section: Introductionmentioning

confidence: 99%

SI113, a Specific Inhibitor of the Sgk1 Kinase Activity that Counteracts Cancer Cell Proliferation

D’Antona

Amato

Talarico

et al. 2015

Cell Physiol Biochem

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Background/Aims:Published observations on serum and glucocorticoid regulated kinase 1 (Sgk1) knockout murine models and Sgk1-specific RNA silencing in the RKO human colon carcinoma cell line point to this kinase as a central player in colon carcinogenesis and in resistance to taxanes. Methods:By in vitro kinase activity inhibition assays, cell cycle and viability analysis in human cancer model systems, we describe the biologic effects of a recently identified kinase inhibitor, SI113, characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold, that shows specificity for Sgk1. Results: SI113 was able to inhibit in vitro cell growth in cancer cells derived from tumors with different origins. In RKO cells, this kinase inhibitor blocked insulin-dependent phosphorylation of the Sgk1 substrate Mdm2, the main regulator of p53 protein stability, and induced necrosis and apoptosis when used as a single agent. Finally, SI113 potentiated the effects of paclitaxel on cell viability. Conclusion:Since SI113 appears to be effective in inducing cell death in RKO cells, potentiating paclitaxel sensitivity, we believe that this new molecule could be efficiently employed, alone or in combination with paclitaxel, in colon cancer chemotherapy.

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Colorectal carcinoma cells—Regulation of survival and growth by SGK1

Cited by 80 publications

References 34 publications

Membrane Androgen Receptor Down-Regulates c-Src-Activity and Beta-Catenin Transcription and Triggers GSK-3beta-Phosphorylation in Colon Tumor Cells

Membrane Androgen Receptor Down-Regulates c-Src-Activity and Beta-Catenin Transcription and Triggers GSK-3beta-Phosphorylation in Colon Tumor Cells

Transcription Factor NF-κB Regulates Expression of Pore-forming Ca2+ Channel Unit, Orai1, and Its Activator, STIM1, to Control Ca2+ Entry and Affect Cellular Functions

SI113, a Specific Inhibitor of the Sgk1 Kinase Activity that Counteracts Cancer Cell Proliferation

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