CXCL12/CXCR4 signaling activates Akt‐1 and MMP‐9 expression in prostate cancer cells: The role of bone microenvironment‐associated CXCL12

Chinni, Sreenivasa R.; Sivalogan, Sivasakthy; Dong, Zhong; Filho, J. Carlos Trindade; Deng, Xiyun; Bonfil, R. Daniel; Cher, Michael L.

doi:10.1002/pros.20318

Cited by 221 publications

(190 citation statements)

References 59 publications

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“…Furthermore, binding of CXCL12 to CXCR4 has been shown to play a crucial role in site-specific metastasis to lymph nodes, lung, and bone (1). In prostate cancer, we and others showed CXCL12/CXCR4 signaling in tumor cells when in bone tissue (2)(3)(4). We also showed that CXCL12/CXCR4 interaction leads to mitogen-activated protein kinase and phosphoinositide 3-kinase/Akt -mediated MMP-9 expression, migration, and invasion of prostate cancer cells (2).…”

Section: Introductionmentioning

confidence: 65%

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Chinni

Yamamoto

Dong

et al. 2008

Molecular Cancer Research

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102

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Chemokines and their receptors function in migration and homing of cells to target tissues. Recent evidence suggests that cancer cells use a chemokine receptor axis for metastasis formation at secondary sites. Previously, we showed that binding of the chemokine CXCL12 to its receptor CXCR4 mediated signaling events resulting in matrix metalloproteinase-9 expression in prostate cancer bone metastasis. A variety of methods, including lipid raft isolation, stable overexpression of CXCR4, cellular adhesion, invasion assays, and the severe combined immunodeficient -human bone tumor growth model were used. We found that (a) CXCR4 and HER2 coexist in lipid rafts of prostate cancer cells; (b) the CXCL12/CXCR4 axis results in transactivation of the HER2 receptor in lipid rafts of prostate cancer cells; (c) Src kinase mediates CXCL12/CXCR4 transactivation of HER2 in prostate cancer cells; (d) a pan-HER inhibitor desensitizes CXCR4-induced transactivation and subsequent matrix metalloproteinase-9 secretion and invasion; (e) lipid raft -disrupting agents inhibited raft-associated CXCL12/CXCR4 transactivation of the HER2 and cellular invasion; (f) overexpression of CXCR4 in prostate cancer cells leads to increased HER2 phosphorylation and migratory properties of prostate cancer cells; and (g) CXCR4 overexpression enhances bone tumor growth and osteolysis. These data suggest that lipid rafts on the cell membrane are the key site for CXCL12/CXCR4 -induced HER2 receptor transactivation. This transactivation contributes to enhanced invasive signals and metastatic growth in the bone microenvironment.

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Section: Introductionmentioning

confidence: 65%

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Chinni

Yamamoto

Dong

et al. 2008

Molecular Cancer Research

Self Cite

116

102

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“…Similarly, stromal cell derived factor and its receptor CXCR4 form a critical regulatory axis for HSC migration, engraftment and homing [88][89][90][91][92], and also function in the metastasis of breast, prostate and other types of cancer [73,[93][94][95][96][97][98][99][100]. Matrix metalloproteinase-9 (MMP-9), belongs to a family of MMPs that plays a critical role during cancer cell invasion [101][102][103][104], and it is also involved in HSC homing and migration [105][106][107]. In addition to providing niches for HSCs, skeletal bones are also the most common sites for cancer metastasis [108].…”

Section: Stem Cell Niche and Tumor Migrationmentioning

confidence: 99%

Beyond tumorigenesis: cancer stem cells in metastasis

et al. 2006

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“…The activation of FAK and Akt has been reported to be closely associated with cell proliferation, anoikis resistance, migration, invasion and stemness of PC cells. [27][28][29][30][31][40][41][42] CXCR4 leads to the activation of diverse intracellular signaling pathways including the Akt pathway, 34,43,44 and CXCL12 evoked increased expression of FAK and enhanced FAK phosphorylation. 35 Furthermore, it has been established that the tumorigenic and metastatic process of PC is regulated by CXCL12/CXCR4 axis.…”

Section: Discussionmentioning

confidence: 99%

“…13 CXCR4 is activated by its exclusive ligand CXCL12, which leads to the activation of diverse intracellular signaling pathways including the Akt pathway. 34 Moreover, CXCL12 evoked FAK upregulation and enhanced FAK phosphorylation. 35 Therefore, CXCR4 could be a missing link between Tpl2 and FAK/Akt.…”

Section: Fak and Akt Mediate Oncogenic Effects Of Tpl2 In Adi Pc Cellsmentioning

confidence: 98%

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Tpl2 induces castration resistant prostate cancer progression and metastasis

Lee

Cho

Lee

et al. 2014

Intl Journal of Cancer

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Progression to metastatic castration resistant prostate cancer (CRPC) is the major lethal pathway of prostate cancer (PC). Herein, we demonstrated that tumor progression locus 2 (Tpl2) kinase is the fundamental molecule provoking progression and metastasis of CRPC. Tpl2 upregulates CXCR4 and focal adhesion kinase (FAK) to activate CXCL12/CXCR4 and FAK/Akt signalling pathway. Consequently, epithelial-mesenchymal transition (EMT) and stemness of androgen depletion independent (ADI) PC cells are induced, which is dependent on the kinase activity of Tpl2. In vitro, proliferation, clonogenicity, migration, invasion and chemoresistance of ADI PC cells were enhanced by Tpl2. In vivo, Tpl2 overexpression and downregulation showed significant stimulatory and inhibitory effects on tumorigenic and metastatic potential of ADI PC cells, respectively. Moreover, the prognostic effects of Tpl2 and expressional correlation between Tpl2 and EMT-related molecules/CXCR4 were validated in clinical PC databases. Since Tpl2 exerts metastatic progression promoting activities in CRPC, Tpl2 could serve as a novel therapeutic target for metastatic CRPC.Prostate cancer (PC) is the most common cancer and second leading cause of cancer-related deaths in males in the United States. 1 Although androgen depletion therapy is highly effective in suppressing PC growth, persistent androgen ablation often results in the development of metastatic castration resistant prostate cancer (CRPC). 2 Currently, patients with metastatic CRPC are treated with taxane-based chemotherapeutic drugs. However, the treatment only serves as a palliative, and distant metastasis is the main cause of PC-related death. 3 Therefore, the identification of novel therapeutic targets in metastatic CRPC is the most urgent clinical requirement that remains unmet.Tumors contain a reservoir of cancer stem cells (CSCs) that are responsible for tumor initiation, progression, metastasis and therapeutic resistance. 4 Since emerging evidence suggests that PC CSCs represent the "bad seeds" of tumor, the molecular mechanisms that maintain PC CSCs could potentially serve as therapeutic targets for metastatic CRPC. 5,6 Although aldehyde dehydrogenase (ALDH) activity 7 and expression of CD44 8 and Bmi-1 9 have been suggested as specific PC CSC markers, using these markers as therapeutic targets is challenging because the molecules lack specific functional and/or enzymatic activities.Tumor progression locus 2 [Tpl2/MAP3 kinase 8 (MAP3K8)], a serine/threonine protein kinase, has been suggested to enhance tumor growth and metastatic progression in distinct types of human cancers. 10-12 Previously, we

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CXCL12/CXCR4 signaling activates Akt‐1 and MMP‐9 expression in prostate cancer cells: The role of bone microenvironment‐associated CXCL12

Cited by 221 publications

References 59 publications

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Beyond tumorigenesis: cancer stem cells in metastasis

Tpl2 induces castration resistant prostate cancer progression and metastasis

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