mTOR Signaling in Cancer Cell Motility and Tumor Metastasis

Zhou, Hongyu; Huang, Shile

doi:10.1615/critreveukargeneexpr.v20.i1.10

Cited by 65 publications

(66 citation statements)

References 148 publications

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“…6 In addition to controlling protein translation and cell growth, S6K1 and mTOR have roles in chemotaxis, cell migration, and tumor cell invasion. [10][11][12] Inhibition of mTOR and S6K1 with rapamycin blocks the growth factor and nutrient mediated migration of intestinal cells, 13 smooth muscle cells, 14 and carcinoma cells on surface substrates such as fibronectin. [15][16][17] As these cells migrate, integrin-mediated signals trigger an activation of mTOR and S6K1, which in turn regulate the remodeling of the actin cytoskeleton to control cell motility.…”

mentioning

confidence: 99%

S6K1 and mTOR regulate Rac1-driven platelet activation and aggregation

Aslan

Tormoen²,

Loren³

et al. 2011

Blood

116

105

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Platelet activation and thrombus formation are under the control of signaling systems that integrate cellular homeostasis with cytoskeletal dynamics. Here, we identify a role for the ribosome protein S6 kinase (S6K1) and its upstream regulator mTOR in the control of platelet activation and aggregate formation under shear flow. Platelet engagement of fibrinogen initiated a signaling cascade that triggered the activation of S6K1 and Rac1. Fibrinogen-induced S6K1 activation was abolished by inhibitors of Src kinases, but not Rac1 inhibitors, demonstrating that S6K1 acts upstream of Rac1. S6K1 and Rac1 interacted in a protein complex with the Rac1 GEF TIAM1 and colocalized with actin at the platelet lamellipodial edge, suggesting that S6K1 and Rac1 work together to drive platelet spreading. Pharmacologic inhibitors of mTOR and S6K1 blocked Rac1 activation and prevented platelet spreading on fibrinogen, but had no effect on Src or FAK kinase activation. mTOR inhibitors dramatically reduced collageninduced platelet aggregation and promoted the destabilization of platelet aggregates formed under shear flow conditions. Together, these results reveal novel roles for S6K1 and mTOR in the regulation of Rac1 activity and provide insights into the relationship between the pharmacology of the mTOR system and the molecular mechanisms of platelet activation. (Blood. 2011;118(11):3129-3136) IntroductionPlatelets represent a specialized set of peripheral blood cells that are optimally configured for adhesion, secretion and aggregation at sites of vascular injury. 1,2 The exposure of platelets to extracellular matrix proteins such as collagen or laminin, or endogenous agonists such as ADP or thromboxanes, mediates hemostasis by activating signaling pathways that ultimately result in platelet adhesion and aggregation. 3 On the engagement of the adhesive proteins fibrinogen and fibronectin, platelet tyrosine kinases such as Src, Syk and FAK are recruited to the platelet cytosolic cell surface to initiate signaling pathways to drive platelet cytoskeletal reorganization through the Rho family small GTPase Rac1. [3][4][5] Rac1 regulates actin polymerization at the cell membrane to drive the growth and extension of platelet lamellipodiae that form the basis for platelet spreading. 4 The molecular mechanisms by which tyrosine kinases ultimately activate Rac1 remain ill-defined.The 70 kDa ribosome S6 protein kinase (S6K1) regulates the ribosome S6 protein to integrate processes of protein translation with cell growth and cell proliferation. 6 In cultured cells as well as in vivo, mitogenic signals triggered by nutrients and growth factors initiate a complex sequence of signaling events to activate the mammalian target of rapamycin (mTOR), a serine/threonine kinase which regulates S6K1 phosphorylation and activation. 7 Treatment of cells with rapamycin (Sirolimus) or other inhibitors of mTOR blocks S6K1 Thr389 phosphorylation and inhibits S6K1 activation. 8 The ability of mTOR inhibitors to arrest the growth of transformed tumor cells with...

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mentioning

confidence: 99%

S6K1 and mTOR regulate Rac1-driven platelet activation and aggregation

Aslan

Tormoen²,

Loren³

et al. 2011

Blood

116

105

View full text Add to dashboard Cite

show abstract

“…mTORC1 integrates signals from growth factor or nutritional status and controls cap-dependent mRNA translation by phosphorylating its substrates 4E-BP1 and S6K1; 4 mTORC2 phosphorylates AKT and SGK1 at a C-terminal site known as the hydrophobic motif and regulates the organization of the actin cytoskeleton, but the biological significance of these activities is not well understood (6,9,10). mTOR plays a critical role in the regulation of tumor cell motility and cancer metastasis (11). However, the underlying mechanism of mTOR regulating cell motility and mTOR inhibitors inhibiting tumor cell motility is understood poorly and controversial (12,13).…”

mentioning

confidence: 99%

Inhibition of Chemokine (CXC Motif) Ligand 12/Chemokine (CXC Motif) Receptor 4 Axis (CXCL12/CXCR4)-mediated Cell Migration by Targeting Mammalian Target of Rapamycin (mTOR) Pathway in Human Gastric Carcinoma Cells

Chen

Wang

et al. 2012

Journal of Biological Chemistry

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CXCL12/CXCR4 plays an important role in metastasis of gastric carcinoma. Rapamycin has been reported to inhibit migration of gastric cancer cells. However, the role of mTOR pathway in CXCL12/CXCR4-mediated cell migration and the potential of drugs targeting PI3K/mTOR pathway remains unelucidated. We found that CXCL12 activated PI3K/Akt/mTOR pathway in MKN-45 cells. Stimulating CHO-K1 cells expressing pEGFP-C1-Grp1-PH fusion protein with CXCL12 resulted in generation of phosphatidylinositol (3,4,5)-triphosphate, which provided direct evidence of activating PI3K by CXCL12. Down-regulation of p110β by siRNA but not p110α blocked phosphorylation of Akt and S6K1 induced by CXCL12. Consistently, p110β-specific inhibitor blocked the CXCL12-activated PI3K/Akt/mTOR pathway. Moreover, CXCR4 immunoprecipitated by anti-p110β antibody increased after CXCL12 stimulation and Gi protein inhibitor pertussis toxin abrogated CXCL12-induced activation of PI3K. Further studies demonstrated that inhibitors targeting the PI3K/mTOR pathway significantly blocked the chemotactic responses of MKN-45 cells triggered by CXCL12, which might be attributed primarily to inhibition of mTORC1 and related to prevention of F-actin reorganization as well as down-regulation of active RhoA, Rac1, and Cdc42. Furthermore, rapamycin inhibited the secretion of CXCL12 and the expression of CXCR4, which might form a positive feedback loop to further abolish upstream signaling leading to cell migration. Finally, we found cells expressing high levels of cxcl12 were sensitive to rapamycin in its activity inhibiting migration as well as proliferation. In summary, we found that the mTOR pathway played an important role in CXCL12/CXCR4-mediated cell migration and proposed that drugs targeting the mTOR pathway may be used for the therapy of metastatic gastric cancer expressing high levels of cxcl12.

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“…mTOR aktivasyonu hücre ölümünü düzenleyen bu molekülleri inhibe etmektedir (3). Yine başka çalışmalarda mTOR'un tümör hücre motilitesinde, anjiyogenezinde ve kanser metastazlarının regülasyonunda önemli rol oynadığı açıklanmıştır (22). Kanser hücrelerinde pek çok farklı mekanizmada PI3K/AKT/ mTOR yolunun yapısal aktivasyonu gözlemlenmektedir.…”

Section: Kanser Tedavisinde Mtor Sinyal Yoluunclassified

“…Bu proteinler sıklıkla malignite oluşumunda, eksikliğe veya mutasyona uğramışlardır ve fonksiyonlarını kaybetmeleri kemoterapiye dirençle ilişkilidir. Örneğin, glikozdan yoksun kalınan koşullarda, kanserde p53 fonksiyonu sıklıkla ortadan kalkar ve böylece bu durum mTOR yapısal aktivasyonunun lehine olabilir (19,22,23 (24,25). Antikanser ajanlar olarak mTOR inhibitörlerinin ortaya çıkışı ana molekülden ziyade rapamisin analogları ile başlamıştır.…”

Section: Kanser Tedavisinde Mtor Sinyal Yoluunclassified

KANSER TEDAVİSİNDE mTOR İNHİBİTÖRLERİ

Özcan¹,

Dikmen²

2015

Marmara Pharm J

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mTOR Signaling in Cancer Cell Motility and Tumor Metastasis

Cited by 65 publications

References 148 publications

S6K1 and mTOR regulate Rac1-driven platelet activation and aggregation

S6K1 and mTOR regulate Rac1-driven platelet activation and aggregation

Inhibition of Chemokine (CXC Motif) Ligand 12/Chemokine (CXC Motif) Receptor 4 Axis (CXCL12/CXCR4)-mediated Cell Migration by Targeting Mammalian Target of Rapamycin (mTOR) Pathway in Human Gastric Carcinoma Cells

KANSER TEDAVİSİNDE mTOR İNHİBİTÖRLERİ

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