Blocking on the CXCR4/mTOR signalling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells

Hashimoto, Isaya; Koizumi, Keiichi; Tatematsu, Mikiko; Minami, T.; Cho, Seiji; Takeno, Nobuhiro; Nakashima, Akitoshi; Sakurai, Hiroaki; Saito, Shigeru; Tsukada, Kazuhiro; Saiki, Ikuo

doi:10.1016/j.ejca.2008.02.043

Cited by 116 publications

(102 citation statements)

References 37 publications

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“…Increased mTOR signaling has been shown to promote more aggressive disease behavior in various cancers such as cervical and gastric cancer, [68][69][70] and the effect of mTOR on cellular function have recently been evaluated in UCC. 71 One recent study has identified phospho-S6-a marker of mTOR activity-expression in 55% of muscle-invasive UCCs, with increased expression evident in paired lymph node metastases.…”

Section: Role Of Mtor In Bladder Cancermentioning

confidence: 99%

Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

Ching

Hansel

2010

Laboratory Investigation

138

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Section: Role Of Mtor In Bladder Cancermentioning

confidence: 99%

Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

Ching

Hansel

2010

Laboratory Investigation

138

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“…mTOR (mammalian target of rapamycin), a conserved serine/threonine kinase, sits in the center of the PI3K-mediated signaling pathways and regulates multiple processes, including mRNA translation, cell cycle progression, cell survival, and motility (5,6). Although it has been reported that CXCL12 activates mTOR (7,8), the precise mechanism underlying activation of the mTOR triggered by CXCL12 in gastric cancer cells remains elusive.…”

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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“…Amongst different types of gastric cancer, peritoneal dissemination is one of the most incurable conditions and no radical and effective treatment is available to date. Hashimoto et al [117] showed that the CXCL12/CXCR4 axis is important in peritoneal dissemination of gastric cancer cells. They found that CXCL12 ligation to CXCR4 on the cancer cell surface strongly and rapidly activates AKT-mammalian target of rapamycin signaling and co-activates production of other metastatic mediators, such as MMPs [117,118] .…”

Section: Stomachmentioning

confidence: 99%

“…Hashimoto et al [117] showed that the CXCL12/CXCR4 axis is important in peritoneal dissemination of gastric cancer cells. They found that CXCL12 ligation to CXCR4 on the cancer cell surface strongly and rapidly activates AKT-mammalian target of rapamycin signaling and co-activates production of other metastatic mediators, such as MMPs [117,118] . Graziosi et al [119] also suggested possible involvement of the p38 MAPK pathway in the development of peritoneal dissemination.…”

Section: Stomachmentioning

confidence: 99%

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Chemokines, chemokine receptors and the gastrointestinal system

Miyazaki¹,

Takabe²,

Yeudall³

2013

WJG

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Core tip: The chemokine network makes an attractive target for therapeutic intervention in many tumor types, including those of the gastrointestinal tract. However, we need to define more selective and specific targets, to minimize systemic side effects during treatment. INTRODUCTION Cancer development and progression in the gastrointestinal tractCancer is a disease in which normal cells acquire genetic and epigenetic abnormalities [1,2] , leading to disorientation of conventional processes for the maintenance of normal cell physiology. These aberrant genetic and epigenetic modifications to the normal cell induce abnormal cell motility, proliferation, and survival, eventually enabling these cells to invade into adjacent tissues and even to migrate to regional or distant organs where they may grow continuously as metastatic lesions [3] . For many cancer patients, metastasis is generally the major cause of disease-related death [4,5] . Therefore, it is indispensable to elucidate the basic molecular mechanisms of tumor development to identify effective therapeutic targets, which can possibly reduce the side-effects of treatment, and define useful molecular markers for early detection and prediction of disease course. Especially, the newly emerged concept of personalized medicine may require in-depth assessment of potential therapeutic molecular target(s) in each individual case through analysis of sig- REVIEW Chemokines, chemokine receptors and the gastrointestinal system AbstractThe biological properties of tumor cells are known to be regulated by a multitude of cytokines and growth factors, which include epidermal growth factor receptor agonists and members of the transforming growth factor β family. Furthermore, the recent explosion of research in the field of chemokine function as mediators of tumor progression has led to the possibility that these small, immunomodulatory proteins also play key roles in carcinogenesis and may, therefore, be potential targets for novel therapeutic approaches. In this review, we will summarize recently reported findings in chemokine biology with a focus on the gastrointestinal tract.

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Blocking on the CXCR4/mTOR signalling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells

Cited by 116 publications

References 37 publications

Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

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

Chemokines, chemokine receptors and the gastrointestinal system

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