Biological Behavior Differences Between Two Colorectual Cancer Cells On Different Cell Differentiation Status With Linoleic Acid Treatments

It is reported that the incidence of cancer worldwild is increasing rapidly in recent years with the promotion of living condition and life style. The incidence of gastrointestinal cancer is rising with the change of diet pattern and lack of exercise. Researches had proved that changes in diet fatty acids composition, raising the ratio of polyunsaturated fatty acids would help in reducing the incidence of gastrointestinal tumors, especially the n-3 polyunsaturated fatty acids. Polyunsaturated fatty acids could also help in tumor cure and prevention of tumor recurrence. In the present work, we analyzed the metabolic pathway of linoleic acid in two colorectural tumor cell lines and a normal cell line HUVEC taken as control to illustrate the mechanisms of cell apoptosis induced by polyunsaturated fatty acids, and try to find if there were differences between different cell lines with different cell differentiation status.Linoleic acid could regulate cell physiological activity after taken in cell by the following four pathways:i) linoleic acid could be stored in cell membrane as phospholipid to modulate cell membrane activity; ii) linoleic acid could be oxidated in mitochondrial and providing ATP for cell energy metabolism; iii) linoleic acid could be transformed into DGLA or AA with the expression of fatty acids desaturases and enlongases; iv) linoleic acid could be transformed into signal molecules to regulate cell viability by COX pathway or LOX pathway. The four functions of linoleic acid existed in cell at the same time and interacted with each other. In the present research, we discussed the cell sensitivity of linoleic acid with different linoleic acid treatments and different cell differentiation status among two colorectual cancer cell lines, LoVo (undifferentiated) and Rko (semi-differentiatied), and one normal cell line HUVEC (human umbilical vein endothelial cell).Our research proved that linoleic acid could affect the cell fatty acids composition by raising the ratio of polyunsaturated fatty acids, especially the n-6 polyunsaturated fatty acids, which could induce the rise of cell membrane fluidity and finally increase the cell membrane permeability by possibly affecting the normal function of cell lipid rafts. Treatment with linoleic acid could affect the expression/activity of fatty acids desaturases and enlongases, so the ratio of long chain fatty acids to cell total fatty acids raised significantly, likewise the ratios of n-6 polyunsaturated fatty acids and n-6/n-3 in cell, while the oxidation of fatty acids was also progressed and the ratio of monounsaturated fatty acids raised in some treatments. Cell viability had inverse relation toΔn-6/n-3 in normal treated cells with all three cell lines, while LoVo could resist to linoleic acid toxin after pre-treatments. So the bioactivity differences of linoleic acid between cells may related to the differences of cell metabolism pathway, and different diet comsumption may lead to different sensitivity of cells to linoleic acid.Additional linoleic acid may affect the cell by initiating free radicals, as different cells have different ways to reduce the cell concentration of free radicals, both LoVo and Rko could accumulate MDA at a relative high level, Rko could also have a significant change in SOD activity, while HUVEC could tolerate a high concentration of linoleic acid. But high concentration could induce mitochondrial damage to all the three cell lines with cytochrome C release and activity of caspase pathway, while LoVo treated with pre-treatment and then high concentration of linoleic acid could survive by inhibiting the activity of caspase-3. So we concluded that the regulation of caspase signal way could affect the cell apoptosis induced by linoleic acid.By analysis of cell energy charge, we found that linoleic acid could affect the normal cell energy metabolism, and this might be caused by the down-regulation of PPARδwith reducing the metabolic of free fatty acid. Linoleic acid could up-regulate the expression of SREBP-2 as it could storage energy by producing high-energy compounds. The up-regulation of SREBP-2, which could compensate for the SREBP-1 down-regulation, could also help in fatty acids synthesis, which may cause the ratio rise of long chain fatty acids in cell. To block the activity of PPARδand SREBP-2 when the tumor cells exposed to PUFAs may reduce the cell viability by regulating the cell energy charge, this would be another way for exploring polyunsaturated fatty acids'function in inducing tumor cell apoptosis.In summary, linoleic acid could induce tumor cell mitochondrial impairment, cell membrane damage, and to some extent have influence to cell energy change. As the apoptosis of tumor cell is a complicated network, the activity of linoleic acid could also modulate the apoptosis in many ways.