1. 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

2. 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 Eur J Cancer
6.8%
7.5%
19.9%
12.3%
The 2014 controlling cancer summit. London, UK
14th may Amr Al-Haidari

3. 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

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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

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

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

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

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

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

16. 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

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