Téma: Molekulární patologie
Číslo abstraktu: 11
Autoři: prof. RNDr. Jiřina Hofmanová, CSc.; Mgr. Nicol Straková, Ph.D.; RNDr. Alena Hyršlová Vaculová, Ph.D.; Mgr. Zuzana Tylichová; Belma Skender; MUDr. Jiří Slavík; RNDr. Miroslav Cigánek, Ph.D.; prof. RNDr. Alois Kozubík, CSc.
Quantity and quality of consumed dietary fat and fibre are considered as important modulators of colon carcinogenesis (CRC). However, the mechanisms of their effects are not fully understood. Specific essential polyunsaturated fatty acids may alter membrane properties, cellular metabolism and intracellular signalling, thus significantly affecting cell behaviour and response to various exogenous or endogenous stimuli. Further, short-chain fatty acid – butyrate (produced by microbial fermentation of fibre in the colon) has antiproliferative and apoptotic effects in colon cancer cells and may influence expression of many important genes. On the other hand, diverse composition, structure, and metabolism of endogenous cellular lipids (lipidome) may predetermine the cell response to dietary fatty acids. Innovative technical approaches enable to uncover an association between the CRC and alterations in cellular lipid composition, metabolism or molecular signalling.
Our detailed analyses of cellular fatty acid (GC/MS) and phospholipid content and composition (LC/MS/MS) showed significant differences among human colon epithelial cell lines derived from fetal colon (FHC), adenomas (AA /C1, RG / C2), adenocarcinomas (HT-29, HCT-116, SW480) or metastasis (SW620). We detected different sensitivity of these cell lines to butyrate and highly unsaturated docosahexaenoic acid (DHA, 22:6, n-3) found mainly in algal and fish oils. After fatty acid treatment also significant changes in cellular fatty acid spectrum and content as well as phospholipid composition were determined. Particularly, the modulations of the amount and spectrum of cardiolipins appear to be important.
Next, we demonstrated an interaction between DHA and butyrate, influencing lipid metabolism (lipid droplet accumulation, expression of fatty acid synthase, fatty acid transporter FAT/CD36, caveolin-1, level and activity of nuclear PPAR gamma receptor), production of reactive oxygen species, mitochondrial events, specific signaling pathways (AMPK, PI3K/Akt), cell cycle and cell death regulators (p21, pro- and antiapoptotic molecules and autophagy markers), and finally cytokinetics (cellular proliferation, differentiation, apoptosis, autophagy). Importantly, we also evidenced the outstanding ability of DHA to sensitize colon cancer cells to the proapoptotic effects of TRAI L (TNF-related apoptosis-inducing ligand), a cytokine of the tumour necrosis factor (TNF) family known for its selective cancer cell toxicity.
Our results highlight the significance of dietary lipids, cellular lipidome and its changes in regulation of colon cell growth and death as well as the cell response to physiological regulatory molecules and potentially promissing anticancer agents.
Supported by grants No. 13-097665 of the Czech Science Foundation and MUNI/A/0927/2013.
Datum přednesení příspěvku: 24. 4. 2014