Abstract 4171: Lipid metabolism-independent role of apolipoprotein (E) levels in colon carcinogenesis through a regulating inflammation and active β-catenin
Authors: Abdelmetalab F. Tarhuni, Ali H. El-Bahrawy, Hogyoung Kim, Youssef Errami, Mohamed A. Ghonim, Mohamed Alwan, Samar M. Hammad, Venkat N. Subramaniama, Ramadan A. Hemeida, Amarjit S. Naura, Hamid A. Boulares
Journal: Cancer Research (2016)

Abstract Apolipoprotein E (ApoE) is critically important for cholesterol metabolism and lipid homeostasis. Polymorphisms in the ApoE gene have been implicated in the development of colon cancer and these polymorphisms may be used as risk indicators for the disease. Accruing evidence suggests new lipid metabolism-independent functions for ApoE both in inflammation and cardiovascular diseases. Ironically, ApoE was shown to up-regulate cyclooxygenase-2 in vascular smooth muscle cells and given the critical role of the COX-2 in colon carcinogenesis, these results suggest a pro-colon cancer function for the lipoprotein. In the present study, we show that a mere deletion of ApoE promotes systemic inflammation as assessed by TNF-α level in sera of mice under a regular diet. Concomitantly, TNF-α mRNA levels were significantly higher in the colon of ApoE-/- mice suggestive of localized inflammation. In contrast to smooth muscle cells, in vitro studies with primary colon epithelial cells (CECs) show that ApoE-deficiency substantially increased COX-2 expression in response to oxidized (ox)LDL both at the protein and mRNA levels. OxLDL-induced expression of COX-2 in WT CECs was highly sensitive to PP2 treatment, a Src inhibitor, and to LY294002, a pan-PI3K inhibitor. Surprisingly, while oxLDL-induced COX-2 expression was sensitive to PI3K inhibition, its sensitivity to Src inhibition was minimal suggesting that ApoE deficiency may promote COX-2 expression through a Src-independent mechanism. Similarly to COX-2, ApoE-deficiency also enhanced basal and ox-LDL-induced expression of MCP-1, IL-1β, ICAM-1, and VCAM-1. Using a cohort of colon cancer patients and healthy controls, we show that the overall levels of ApoE in sera of colon cancer patients were significantly lower than those of healthy controls (p = 0.0028). We have utilized ApcMin mice, well-characterized mouse model of intestinal tumor. Using this genetic background, we have generated ApoE+/- and ApoE-/- lines which were utilized in this study. We found that inhibition of ApoE through gene heterozygosity led to ∼50% reduction in the level of ApoE protein and a significant increased the number tumors in these mice compared to their wildtype counterparts. These changes in tumor burden were accompanied by slight changes in the lipid profiles of the ApoE+/- mice. Surprisingly however, when examining the results of ApoE-/-, we found that the tumor burden was not increased over that seen in the ApoE heterozygous mice, but the lipid profiles were elevated dramatically. This suggests that the mechanism through which ApoE affects lipid metabolism is separate from that which is involved in the formation of colon tumors. This aggravation of the tumor burden may be associated with a stimulus-independent increase in the levels of the active form of β-catenin. These results suggest that ApoE deficiency may be informative for the risk of developing colon cancer. Citation Format: Abdelmetalab F. Tarhuni, Ali H. El-Bahrawy, Hogyoung Kim, Youssef Errami, Mohamed A. Ghonim, Mohamed Alwan, Samar M. Hammad, Venkat N. Subramaniama, Ramadan A. Hemeida, Amarjit S. Naura, Hamid A. Boulares. Lipid metabolism-independent role of apolipoprotein (E) levels in colon carcinogenesis through a regulating inflammation and active β-catenin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4171.