The Ras superfamily of small GTPases control a wide range of cellular processes by switching between inactive GDP- and active GTP-bound states. These active proteins regulate cell behavior by binding to effector molecules and changing their location, activity and protein-protein interactions. Mutated versions of the Ras genes were first identified in human cancers over 20 years ago and the importance of aberrant Ras activation in oncogenesis is well established. Members of both the Ras and Rho subfamilies affect cell proliferation. More recently it has been suggested that Ras and Rho signaling pathways crosstalk in such a way as to favor transformation and cell proliferation. Exactly how these two Ras superfamily members communicate is not entirely clear. One recent study indicated that in NIH 3T3 cells oncogenic Ras activates RhoA by inhibiting Ras induced p190Rho-GAP sequestration in a detergent resistant membrane (DRM) fraction. We have demonstrated that the dietary long chain saturated fatty acid, stearate (C18:0), found in meat and chocolate, inhibits breast cancer cell proliferation. Our preliminary data indicate that this inhibition of cell proliferation is accompanied by an arrest of the cell cycle, an increase in Ras activity, and a decrease in Rho activity. In other studies we have demonstrated that stearate is capable of selectively regulating the movement of annexin II into DRM. Our preliminary data indicates that stearate is capable of inhibiting p190 Rho-GAP from locating in DRM. Our hypothesis is that stearate inhibits Rho activity by inhibiting p190Rho- GAP sequestration in DRM. The goal of this proposal is to confirm that stearate induced p190 Rho-Gap inhibition of Rho activity is responsible for cancer cell cycle arrest, determine whether dietary stearate inhibits Ras mediated mammary tumors in vivo and characterize stearate inhibition of Rho activity including determining the mechanism of action and whether stearate inhibits the proliferation of other cancer and non- cancer cell types. These studies are significant because they represent the first mechanistic evidence of a nutrient interfering with Ras-Rho crosstalk and may represent a novel dietary approach to the inhibition of cancer progression. ?
| Li, Chuanyu; Zhao, Xiangmin; Toline, Eric C et al. (2011) Prevention of carcinogenesis and inhibition of breast cancer tumor burden by dietary stearate. Carcinogenesis 32:1251-8 |
| Evans, Lynda M; Cowey, Stephanie L; Siegal, Gene P et al. (2009) Stearate preferentially induces apoptosis in human breast cancer cells. Nutr Cancer 61:746-53 |
