Abstract B02: Disruption of lipid rafts constituents and implications for the cancer promotion properties of the carcinogenic mycotoxin, fumonisin B1

Abstract

Abstract Substantial evidence links food as a source of natural occurring carcinogens with the incidence of cancer in humans. The carcinogenic group 2B mycotoxin, fumonisin B1 (FB1) is a natural occurring toxin, produced by different Fusarium species in maize. In South African rural maize-subsistence farming communities, the chronic exposure to high levels of fumonisin is epidemiologically linked to a high prevalence of oesophageal cancer (OC). Despite no direct association with the etiology of OC, FB1 has been identified as a liver cancer promoter involving the disruption of the lipid metabolism. Subsequently the disruption of the membrane integrity and function has been proposed as a possible mechanism for cancer promotion by fumonisin. The presence of highly specialized and functional lateral assemblies or microdomains on cell membranes surfaces has provided an additional platform to investigate the effect of FB1 on cancer promotion. Rat primary hepatocytes were exposed to FB1 (250 μM associated with moderate cytotoxicity) for 24hrs at 37°C, followed by lipid raft isolation using a non-detergent method. Characterization of major lipids such as cholesterol (CHOL), sphingomyelin (SM), phosphatidylcholine (PC), phosphatidylethanolamine (PE) was determined. Raft CHOL isolated from treated hepatocytes, significantly (p<0.05) increased (93.0 ± 8.7 95%CI 71.3-114.4) in contrast to the untreated cells (53.5 ± 5.5 95%CI 40.0-67.0). Similarly, an increase (p<0.05) in raft PE levels were observed in the treated cells (56.6 ± 0.1 95%CI 32.0-81.3) compared to the untreated cells (36.4 ± 0.1 95%CI 36.0-36.7 while PC were unchanged. Whereas the raft SM content of FB1 treated rat primary hepatocytes (12.5 ± 2.0, 95%CI 7.6-17.4) were significantly reduced compared to that of the untreated cells (29.3 ± 9.9, 95%CI 19.2-39.3). These changes resulted in a decrease in important membrane fluidity parameters including the PC/PE and CHOL/PL (with PL = PC + PE) ratios and suggest an increase in raft rigidity. Major fatty acid (FA) changes in the PC include a decreased in total saturated FAs (SFAs), monounsaturated FAs (MUFAs) and n-3 FA content while in PE, the total MUFAs and polyunsaturated FAs (PUFAs) increased. The subsequent decrease of C18:1n-9 in PC, known to exhibit antioxidant properties, and the increase in C20:4n-6 and total n-3 PUFAs (C22:5n-3 and C22:6n-3) in PE is suggestive of an enhanced sensitivity to oxidative stress known to be effected by FB1 in the liver The cumulative FB1-induced disruption important raft constituents and their FA content, suggests an altered raft liquid-ordered complex architecture that may deferentially affect cell survival indices in normal and cancer cells. Modulation of these major lipid raft constituents is likely to be key determinants underlying the cancer promotional effects of FB1 in the liver by the sensitizing normal hepatocytes to apoptotic responses with a selective resistance of altered pre-neoplastic cells. Citation Format: Hester-Mari Burger, Stefan Abel, Wentzel CA Gelderblom. Disruption of lipid rafts constituents and implications for the cancer promotion properties of the carcinogenic mycotoxin, fumonisin B1 [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B02.