Rapid activation of FAK/mTOR/p70S6K/PAK1-signaling controls the early testosterone-induced actin reorganization in colon cancer cells

Gu, Shuchen; Kounenidakis, Michalis; Schmidt, Eva-Maria; Deshpande, Divija; Alkahtani, Saad; Alarifi, Saud; Föller, Michael; Alevizopoulos, Konstantinos; Läng, Florian; Stournaras, Christos

doi:10.1016/j.cellsig.2012.08.005

Cited by 44 publications

(47 citation statements)

References 29 publications

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“…Sun et al (21) suggested that wogonoside induces autophagy through regulating the mitogen-activated protein kinase-mTOR signaling pathway in MDA-MB-231 cells. P70S6K, the kinase of 40S ribosomal small subunit protein S6 and one of the downstream targets in the PI3K/Akt/mTOR signaling pathway, directly phosphorylates 40S ribosomal protein S6 to promote the translation of mRNA essential in the Gl-S stage of the cell cycle, as well as the expression of proteins associated with cell growth and differentiation, thus serving an important role in the regulation of cell growth and proliferation (29,30). The mTOR/P70S6K signaling pathway serves an essential role in cell growth, differentiation, proliferation, migration and survival (29).…”

Section: Discussionmentioning

confidence: 99%

“…P70S6K, the kinase of 40S ribosomal small subunit protein S6 and one of the downstream targets in the PI3K/Akt/mTOR signaling pathway, directly phosphorylates 40S ribosomal protein S6 to promote the translation of mRNA essential in the Gl-S stage of the cell cycle, as well as the expression of proteins associated with cell growth and differentiation, thus serving an important role in the regulation of cell growth and proliferation (29,30). The mTOR/P70S6K signaling pathway serves an essential role in cell growth, differentiation, proliferation, migration and survival (29). Zhang et al (31) reported wogonoside induces autophagy-related apoptosis in human glioblastoma cells through the PI3K/AKT/mTOR/p70S6K signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

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Wogonoside inhibits cell growth and induces mitochondrial-mediated autophagy-related apoptosis in human colon cancer cells through the PI3K/AKT/mTOR/p70S6K signaling pathway

et al. 2018

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Abstract. Wogonoside, the main effective constituent of traditional Chinese medicine Scutellaria, belongs to the glucuronide family, with various functions, including detoxification, anti-inflammation and nourishing gallbladder, lowering blood pressure, diuresis and anti-allergic reactions. However, the effects of wogonoside on human colon cancer cells remain unclear. The present study aimed to investigate the anticancer effect of wogonoside on human colon cancer cells in vitro and its anticancer mechanisms. The results demonstrated that wogonoside significantly inhibited cell growth, induced apoptosis and mitochondrial-mediated autophagy of colon cancer cells. Furthermore, the results revealed that wogonoside significantly increased caspase-3 and caspase-9 expression levels, induced apoptosis regulator Bax/Bcl-2 and microtubule-associated protein 1A/1B-light chain 3 protein expression, suppressed the phosphatidylinositol 3 kinase (PI3K)/RAC-α serine/threonine-protein kinase (Akt)/mechanistic target of rapamycin (mTOR)/p70 S6 kinase (p70S6K) signaling pathway and induced p62 protein expression in colon cancer cells. In conclusion, these results demonstrated that wogonoside inhibits cell growth and induces mitochondrial mediated autophagy-related apoptosis in human colon cancer cells through modulation of the PI3K/Akt/mTOR/p70S6K signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Wogonoside inhibits cell growth and induces mitochondrial-mediated autophagy-related apoptosis in human colon cancer cells through the PI3K/AKT/mTOR/p70S6K signaling pathway

et al. 2018

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“…30 The mAR-dependent signaling, resulting in profound actin reorganization, was recently characterized in detail in prostate, breast and colon tumor cells. 8,15 Furthermore, it was shown that mAR activation induced profound apoptotic regression of prostate and colon cancer cells in vitro and in mouse xenograftsin vivo 2,6,12,13 and suppressed cell growth and motility. 5,6,13,14 These effects were regulated by the mAR-governed actin reorganization.…”

Section: Discussionmentioning

confidence: 99%

“…13,14 In a recent study, we have described the signaling pathway governing the mAR-induced effects on actin restructuring in colon tumor cells. 15 This pathway involves rapid activation of FAK, mTOR, p70S6K and the actin regulating protein PAK1. Interestingly, experiments using specific inhibitors indicated that the Rho/ROCK signaling may not be involved in colon tumor cells, although this pathway was activated in prostate cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Testosterone induced apoptosis in colon cancer cells is regulated by PI3K/Rac1 signaling

Alkahtani¹

2013

Asian J Androl

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Recently, it has been reported that testosterone membrane signaling regulates actin reorganization and induces pro-apoptotic responses in colon tumor cells. In the present study the membrane androgen receptors (mARs)-induced activation of Rac1 GTPase and the involvement of PI3K/Rac1 signaling in controlling the apoptotic responses in testosterone treated Caco2 colon cancer cells has been analyzed. In line with previous findings, activation of mAR by testosterone conjugates triggered early and transient actin reorganization as indicated by the significant decrease of the G/Total actin ratio after 15-and 30-min treatment of the cells. Interestingly, stimulation of mAR rapidly activated the Rac1 GTPase. This effect was evident after 15 min and persisted for at least 24 h. Testosterone induced Rac1 activation was fully blocked in Caco2 cells pre-treated with the PI3K inhibitor wortmannin, indicating that Rac1 signaling is acting downstream of the PI3K pathway. Remarkably, when cells were pre-treated with wortmannin that blocks the PI3K/Rac1 signaling, apoptotic response was almost fully inhibited. These finding suggest that Rac1 activation, triggering actin redistribution, is involved in testosterone induced pro-apoptotic responses governed by mAR activation and emphasize the regulatory role of PI3K/Rac1 signaling in colon tumors.

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“…Although we did not investigate this further, PAK1 mediates the effects of both testosterone and estrogen (35,36). Therefore it is not surprising that PAK1 may play a gender-specific role in colorectal tumorigenesis.…”

Section: Discussionmentioning

confidence: 92%

PAK1 Promotes Intestinal Tumor Initiation

Dammann

Khare

Harpain

et al. 2015

Cancer Prevention Research

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p21-activated kinase 1 (PAK1) is a serine/threonine kinase that is overexpressed in colorectal cancer. PAK1 is a target of mesalamine [5-aminosylicylic acid (5-ASA)], a common drug for the treatment of ulcerative colitis with prospective chemopreventive properties. Here, we investigated whether PAK1 deletion impedes tumorigenesis in murine intestinal cancer models. Ten-week-old APC min or APC min /PAK1 À/À mice were monitored for 8 weeks, euthanized, and assessed for tumor number and size. Six-to 8-week-old PAK1 À/À and wild-type (WT) mice received one 10 mg/kg intraperitoneal injection of azoxymethane (AOM) and four cycles of 1.7% dextran sodium sulfate (DSS) for 4 days followed by 14 days of regular water. Mice also received 5-ASA via diet. Tumor incidence and size was assessed via colonoscopy and pathology. Molecular targets of PAK1 and 5-ASA were evaluated via immunohistochemistry (IHC) in both models. PAK1 deletion reduced tumor multiplicity and tumor burden but did not alter average tumor size in APC min mice. IHC revealed that PAK1 deletion reduced p-AKT, b-catenin, and c-Myc expression in APC min adenomas. Colonoscopy and pathologic analysis revealed that PAK1 deletion reduced tumor multiplicity without affecting tumor size in AOM/DSS-treated mice. 5-ASA treatment and PAK1 deletion impeded tumor multiplicity and dysplastic lesions in AOM/DSS mice. IHC further revealed that 5-ASA blocked b-catenin signaling via inhibition of PAK1/p-AKT. These data indicate that PAK1 contributes to initiation of intestinal carcinogenesis.

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Rapid activation of FAK/mTOR/p70S6K/PAK1-signaling controls the early testosterone-induced actin reorganization in colon cancer cells

Cited by 44 publications

References 29 publications

Wogonoside inhibits cell growth and induces mitochondrial-mediated autophagy-related apoptosis in human colon cancer cells through the PI3K/AKT/mTOR/p70S6K signaling pathway

Wogonoside inhibits cell growth and induces mitochondrial-mediated autophagy-related apoptosis in human colon cancer cells through the PI3K/AKT/mTOR/p70S6K signaling pathway

Testosterone induced apoptosis in colon cancer cells is regulated by PI3K/Rac1 signaling

PAK1 Promotes Intestinal Tumor Initiation

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