| Budget Amount *help |
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2005: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2004: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
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| Research Abstract |
Rho GTPases play an essential role in the control of various cellular functions. Accumulating evidence suggests that RhoA overexpression contributes to human cancer development. However, the activation states of RhoA are poorly defined in cancer cells. In this study, we examined both the expression levels and the activation states of RhoA and its upstream activator, RhoGEFs, in various lung cancer cells. Additionally, we analyzed the mechanisms of RhoA activation in these cells to search for new molecular targets for lung cancer treatment. We found that RhoA is activated in various lung cancer cells independent of its expression levels. Especially, the activation status of RhoA is higher comparing to its expression levels in small cell lung cancer (SCLC) cells. Next, we measured the expression levels of three RGL-domain containing RhoGEFs: p115RhoGEF, LARG, and PDZ-RhoGEF, as a candidate for direct activator of RhoA in these cancer cells for the first time. We found that LARG is strongly expressed in all types of lung cancer cells, suggesting the importance of LARG in lung cancer pathogenesis. Finally, we dissected the signaling pathway from cell surface receptor to Rho in SCLC cells using broad-spectrum GPCR antagonist and recently reported Gαq-selective inhibitor. We found that the high activation state of RhoA in SCLC cells mainly depends on a neuroendocrine peptide autocrine system which signals through Gα12 coupled GPCR to RhoA. These results suggest that inhibition of this signaling pathway will be the possible new strategies for targeted lung cancer therapy.
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