Kisspeptin-10-Induced Signaling of GPR54 Negatively Regulates Chemotactic Responses Mediated by CXCR4: a Potential Mechanism for the Metastasis Suppressor Activity of Kisspeptins

Navenot, Jean-Marc; Wang, Zixuan; Chopin, Michaël; Fujii, Nobutaka; Peiper, Stephen C.

doi:10.1158/0008-5472.can-05-1757

Cited by 84 publications

(76 citation statements)

References 32 publications

(37 reference statements)

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“…Kisspeptin receptor stimulation has been demonstrated to inhibit calcineurin activity (Stathatos et al, 2005), which could also contribute to metastasis suppression. The kisspeptin receptor pathway seems to have the ability to disrupt signaling via the chemokine receptor CXCR4, thus inhibiting the prometastatic activity arising from interaction with its ligand, stromal cell-derived factor 1 (Navenot et al, 2005). Kisspeptin has been reported to induce apoptosis in cells, although there are conflicting reports about the role apoptosis may play in the metastasis-suppressing actions of kisspeptin (Harms et al, 2003;Becker et al, 2005).…”

Section: Receptor Signalingmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXVII. Kisspeptin Receptor Nomenclature, Distribution, and Function

Kirby

Maguire²,

Colledge³

et al. 2010

Pharmacol Rev

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Section: Receptor Signalingmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXVII. Kisspeptin Receptor Nomenclature, Distribution, and Function

Kirby

Maguire²,

Colledge³

et al. 2010

Pharmacol Rev

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“…GPR54 activation by kisspeptins was shown to block chemotaxis to fetal bovine serum, activate extracellular signal-regulated kinase (ERK) mitogenactivated protein kinase, induce formation of stress fibers, phosphorylate focal adhesion complex, decrease expression of matrix metalloproteinase 9, and reduce cell proliferation in receptor transfectants (Kotani et al, 2001;Ohtaki et al, 2001;Yan et al, 2001). We have shown previously that activation of GPR54 by kisspeptin-10 (Kp-10) inhibited chemotaxis induced by stromal cell-derived factor 1/CXCL12 and its receptor CXCR4 (Navenot et al, 2005), a mechanism shown in several models to be involved in the migration of CXCR4ϩ tumor cells to the organs that secrete its ligand such as the lungs, liver, brain, and bones (Mü ller et al, 2001). Activation of GPR54 suppressed Akt phosphorylation by CXCR4 (Navenot et al, 2005).…”

mentioning

confidence: 99%

Activation of Rho and Rho-Associated Kinase by GPR54 and KiSS1 Metastasis Suppressor Gene Product Induces Changes of Cell Morphology and Contributes to Apoptosis

Navenot¹,

Fujii²,

Peiper³

2009

Mol Pharmacol

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The mechanism of action of the metastasis suppressor KiSS1 and its receptor GPR54 is still incompletely characterized. Although the loss of KiSS1 expression by tumor cells has been associated with a metastatic phenotype, the nature of the cellular target of the secreted kisspeptins is unknown. Although an autocrine model of action has been generally assumed, metastasis suppression by KiSS1 has also been shown in cells that do not express GPR54, suggesting a paracrine mechanism in which kisspeptins affect cells in the metastatic niche. Activation of GPR54 was shown to inhibit cell motility and invasion of tumor cells, induce the formation of stress fibers, and reduce the expression of matrix metalloproteinase 9. We showed previously that the activation of GPR54 by kisspeptin-10 suppressed CXCR4-mediated chemotaxis in response to stromal cell-derived factor 1/CXCL12 and abolished the phosphorylation of Akt by CXCR4. We also demonstrated that activation of GPR54 inhibited Akt phosphorylation after the activation of epidermal growth factor receptor and the insulin receptor and triggered apoptosis in epithelial and lymphoid cell lines through a mechanism involving extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase. We show here that the activation of GPR54 induced immediate and profound changes of cell morphology, including cytoplasmic condensation and formation of unpolarized plasma membrane protrusions. These events were dependent on Rho and Rho-Associated Kinase (ROCK) activation. The activation of ROCK also contributed to GPR54-mediated apoptosis in 293 cells, and its effect was additive to and independent of ERK activation. These results suggest that RhoA and ROCK are additional key components of the antimetastatic effect of kisspeptins.KiSS1 was identified as a metastasis suppressor gene in human malignant melanoma cells (Welch et al., 1994;Lee et al., 1996). As opposed to tumor suppressors, metastasis suppressors do not inhibit the growth of primary tumors but specifically target the spread of tumor cells to distant organs and the establishment of secondary lesions. These metastasis suppressors can interfere with any step of the metastatic cascade, including invasion, angiogenesis, migration and homing, intravasation, survival, and proliferation in a new environment (Stafford et al., 2008). The metastatic phenotype may be conferred by the expression of a limited number of genes, including the chemokine receptor CXCR4, which has been shown to program organ-specific metastatic spread by multiple malignant tumor cell types (Kang et al., 2003;Minn et al., 2005). Other genes that contribute to the metastatic phenotype are involved in establishing a supportive microenvironment (Minn et al., 2005).KiSS1 was originally identified in experiments in which the transfer of human chromosome 6 to metastatic melanoma cells suppressed metastasis in a mouse xenograft model (Welch et al., 1994;Lee et al., 1996). The gene was identified by subtractive hybridization and differential display and w...

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“…BRMS1 and CXCR4 are also inversely correlated in non-small cell lung cancer cases indicating that one mechanisms of BRMS1 suppression of metastasis is downregulation of CXCR4. KISS1, and protease cleavage-derived kisspeptins, prevent SDF-1 induced CXCR4 chemotaxis (41). While further studies will be required to establish definitive connections between CXCR4, KISS1/BRMS1 and metastasis suppression, the implications provide testable hypotheses regarding mechanisms of metastasis suppression.…”

Section: Discussionmentioning

confidence: 99%

“…Both metastasis suppressors significantly reduce (or prohibit) tumor cell proliferation in ectopic sites (22,39). Intriguingly, BRMS1 and KISS1 both regulate CXCR4 signaling (40,41). In non-small cell lung cancer, BRMS1 reduces CXCR4 expression through inhibition of NFκB resulting in an inhibition of SDF-1 induced migration (40).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of CXCR4 by CTCE-9908 inhibits breast cancer metastasis to lung and bone

Richert

Vaidya²,

Mills³

et al. 2009

Oncol Rep

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Abstract. Metastasis occurs, in part, due to tumor cell responses to chemokine secretion by ectopic organs or tissues. SDF-1 is constitutively expressed in tissues where metastases frequently develop while breast carcinoma cells express the receptor for SDF-1, CXCR4, which is correlated with increased bone metastasis and poor overall survival. We hypothesized that treatment with a CXCR4 antagonist, CTCE-9908, would decrease incidence of bone and lung metastasis. Treatment with CTCE-9908 (25 mg/kg) began the day prior to or the day of intravenous or intracardiac tumor cell inoculation of MDA-MB-231 human breast carcinoma cells expressing enhanced green fluorescent protein (GFP) into athymic mice. After 5 or 8 weeks (i.c. and i.v. injections, respectively), the presence of fluorescent foci at metastatic sites was assessed. Somewhat surprisingly, CTCE-9908 treatment did not decrease incidence of metastasis as hypothesized. However, CTCE-9908 did decrease metastatic burden (i.e., size of metastases) in all organs examined (lungs, bone, heart, liver, kidneys, pancreas and spleen). Based upon this and other studies, the use of CTCE-9908 is promising as an adjuvant therapy for metastatic disease.

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Kisspeptin-10-Induced Signaling of GPR54 Negatively Regulates Chemotactic Responses Mediated by CXCR4: a Potential Mechanism for the Metastasis Suppressor Activity of Kisspeptins

Abstract: The product of the KiSS-1 gene is absent or expressed at low level in metastatic melanoma and breast cancer compared with their nonmetastatic counterparts. A polypeptide derived from the KiSS-1 product, designated kisspeptin-10

Cited by 84 publications

References 32 publications

International Union of Basic and Clinical Pharmacology. LXXVII. Kisspeptin Receptor Nomenclature, Distribution, and Function

International Union of Basic and Clinical Pharmacology. LXXVII. Kisspeptin Receptor Nomenclature, Distribution, and Function

Activation of Rho and Rho-Associated Kinase by GPR54 and KiSS1 Metastasis Suppressor Gene Product Induces Changes of Cell Morphology and Contributes to Apoptosis

Inhibition of CXCR4 by CTCE-9908 inhibits breast cancer metastasis to lung and bone

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