Activation of Rho and Rho-associated kinase by GPR54 and KiSS1 metastasis suppressor gene product induces changes of cell morphology and contributes to apoptosis.
Navenot. Jean-Marc JM; Fujii. Nobutaka N; Peiper. Stephen C SC
Key Findings
- Kisspeptin‑10 activation of GPR54 triggers rapid Rho and ROCK activation, causing dramatic cell‑shape changes.
- Rho/ROCK signaling contributes to apoptosis in a way that adds to, but is separate from, ERK‑mediated pathways.
- RhoA and ROCK are identified as key players in the anti‑metastatic actions of kisspeptins.
Practical Outcomes
- At this stage there’s no direct protocol for biohackers; the work mainly adds mechanistic insight that could guide future drug development. It suggests that combining kisspeptin‑based approaches with Rho/ROCK modulation might be a future anti‑cancer strategy, but more research is needed before any safe human use.
Summary
Kisspein‑10 binds to its receptor GPR54 on cells, quickly turning on the Rho/ROCK signaling pathway, which makes the cells change shape and eventually die. This cell‑killing effect may help stop cancer cells from spreading, but the study is done in lab dishes and doesn’t give any dosing or safety info for people.
Abstract
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.
Study Information
pubmed
2009
2009-03-13T00:00:00.000Z
10.1124/mol.109.055095
47
40