HMG-COA reductase regulates CCL17-induced colon cancer cell migration via gernaylgeranylation and RhoA activation Amr Al-Haidari Department of Clinical.

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Presentation transcript:

HMG-COA reductase regulates CCL17-induced colon cancer cell migration via gernaylgeranylation and RhoA activation Amr Al-Haidari Department of Clinical Sciences, Surgery Research Unit, Lund University, Sweden The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari

Background CRC is the 2nd leading cause of cancer related death in Europe where 90% of death cases are due to tumor metastasis. Ferlay J et al. Eur J Cancer Patrick Mehlen & Alain Puisieux. Nature Reviews Cancer Lung CRC Breast Prostate Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 6.8% 7.5% 19.9% 12.3% The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari

Background Chemokines are inflammatory mediators that regulate leukocyte migration to the site of inflammation. Tumor cells can express Chemokine receptors e.g. CXCL12/CXCR4 axis in colorectal cancer, breast cancer and multiple myeloma Rubie et al. Journal of Translational Medicine 2011 Abdel Kareem Azab et al. Blood. 2009 The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari

Background The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari

CCR4 mediates CCL17 (TARC)-induced migration of human colon cancer cells via RhoA/Rho-kinase signaling. Al Haidari et al. InJ Colorectal Dis The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari

CCR4 mediates CCL17 (TARC)-induced migration of human colon cancer cells via RhoA/Rho-kinase signaling. Al Haidari et al. InJ Colorectal Dis The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari

CCR4 mediates CCL17 (TARC)-induced migration of human colon cancer cells via RhoA/Rho-kinase signaling. Al Haidari et al. InJ Colorectal Dis The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari

Isoprenylation Acetyl-CoA Mevalonate farnesylation Geranylgeranylation RhoA GDP GEF GAP GTP Down steam effectors Extracellular Intracellular Inactive Active Isoprenylation cytoskeleton reorganization And stress fibers formation farnesylation Geranylgeranylation Acetyl-CoA Mevalonate HMGCoA reductase The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari

What is New Simvastatin inhibits colon cancer migration in response to chemokine/chemokine receptor signaling The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari

Aim of the study To understand the molecular basis of tumor cell migration under Simvastatin treatment The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari

Simvastatin decreased colon cancer cell migration in vitro The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari

Simvastatin has no effect on tumor cell apoptosis and proliferation The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari

GGPP recovered Simvastatin-incuced inhibition of active RhoA The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari

GGPP reversed the effect of simvastatin-induced inhibition of tumor cell migration The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari

CCR4 antagonist reduced CCL17-incuced increased active RhoA The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari

Simvastatin is a potential anti-metastatic agent in Colon cancer. Conclusions CCL17/CCR4 axis is implicated in colon cancer cell migration through RhoA activation Simvastatin can inhibit tumor cell migration independently from its pro-apoptotic activity The inhibitory effect of Simvastatin on migration of colon cancer cells may be mediated by geranylgeranylation Simvastatin is a potential anti-metastatic agent in Colon cancer. The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari

Thank you.. The 2014 controlling cancer summit. London, UK 14th may Amr Al-Haidari