Elaidic Acid, a Trans-Fatty Acid, Enhances the Metastasis of Colorectal Cancer Cells.

The effects of trans-fatty acids (TFAs) on cardiovascular disorders have been extensively studied, and the effect of TFAs on cancers has recently been recognized. This study examined the effects of elaidic acid (EA), a TFA, on colorectal cancer (CRC) progression. We demonstrated that EA enhanced the growth, survival, and invasion of the CRC cell lines, CT26, and HT29. Tumor growth and metastasis in the lung, liver, and peritoneum were significantly more enhanced in CRC cells treated with EA than those treated with the cis form of EA, oleic acid (OA), or vehicle. Spheres of CRC cells were formed at more pronounced numbers in EA-treated cells than in OA-treated cells. Compared to OA, EA treatment also induced expression of the stemness factors, nucleostemin, CD133, and Oct4. Moreover, spheres of EA-treated CRC cells were larger and more proliferative than spheres of OA-treated cells. Oral intake of EA also enhanced liver metastasis and CD133 expression of CRC cells in a dose-dependent manner. EA intake also increased resistance to 5-fluorouracil. Inhibition of Wnt and ERK1/2 abrogated EA-induced enhancement of metastasis. Our findings demonstrate that EA might provide prominent metastatic potential to CRC cells, which shows important implications for the treatment of CRC.

Diverse effects of G-protein-coupled free fatty acid receptors on the regulation of cellular functions in lung cancer cells.

Free fatty acids (FFAs) are dietary nutrients which mediate a variety of biological effects through binding to G-protein-coupled FFA receptors (FFARs). G-protein-coupled receptor 120 (GPR120) and GPR40 are identified as FFARs for long- and medium-chain fatty acids. Here we investigated whether GPR120 and GPR40 are involved in the acquisition of malignant properties in lung cancer cells. Three lung cancer RLCNR, LL/2 and A549 cells used in this study expressed GPR120 and GPR40 genes. The cell motile activities of all cells were significantly suppressed by a GPR40 antagonist GW1100. In addition, GPR40 knockdown inhibited the cell motile activity of A549 cells. In gelatin zymography, matrix metalloproteinase-2 (MMP-2) activity in GPR40 knockdown was significantly lower than that in control cells. Next, to evaluate effects of GPR120 and GPR40 on cellular functions induced by anti-cancer drug, the long-term cisplatin (CDDP) treated (A549-CDDP) cells were generated. The expression levels of GPR120 and GPR40 were significantly decreased in A549-CDDP cells. While A549-CDDP cells showed the high cell motile activity, GW1100 suppressed the cell motile activity of A549-CDDP cells. These results demonstrate that GPR120 negatively and GPR40 positively regulate cellular functions during tumor progression in lung cancer cells.

Remodeling of energy metabolism by a ketone body and medium-chain fatty acid suppressed the proliferation of CT26 mouse colon cancer cells.

Normal and cancerous cells are suggested to have differential utilization of fatty acids and ketone bodies, which could be exploited in cancer therapy. The present study examined the effect of 3-hydroxybutyric acid (3-HBA), which is a ketone body generating acetyl-CoA, and lauric acid (LAA, C12:0), which is a medium-chain saturated fatty acid translocated to mitochondria in a carnitine-independent manner to produce acetyl-CoA, on the energy metabolism of mouse CT26 colon cancer cells. In CT26 cells expressing 3-HBA and LAA transporters, 3-HBA and LAA reduced cell proliferation, mitochondrial volume and lactate production, and increased oxidative stress, particularly in low-glucose conditions. Concurrent treatment with 3-HBA and LAA under glucose starvation had a synergistic effect on cell growth inhibition. In addition, LAA and LAA + 3-HBA promoted an imbalance in the expression of enzymes in the electron transport chain. These findings suggested that treatment with 3-HBA and/or LAA during glucose starvation may reprogram energy metabolism and decrease the proliferation of cancer cells.

Fatty acids inhibit anticancer effects of 5-fluorouracil in mouse cancer cell lines.

The present study investigated the effects of two major dietary fatty acid components, linoleic acid (LA) and elaidic acid (EA), on the antitumor effects of 5-fluorouracil (5-FU) in the LL2, CT26 and CMT93 mouse cancer cell lines. Concurrent treatment with LA and 5-FU elicited a decreased cell viability compared with treatment with 5-FU alone. In addition, increased inhibition of growth was observed following concurrent treatment with EA and 5-FU. Sequential treatment of LA followed by 5-FU abrogated the anticancer effects of 5-FU, and treatment with EA followed by 5-FU increased cancer cell growth in addition to abrogating the anticancer effects of 5-FU. The expression of the stem cell markers CD133 and nucleostemin (NS) increased in all three cell lines treated concurrently with 5-FU and either LA or EA when compared with cells treated with 5-FU alone. Aldehyde dehydrogenase activity in the cancer stem cells (CSCs), in response to concurrent treatment with 5-FU and either LA or EA, was increased compared with 5-FU treatment alone. 5-FU inhibited the growth of CT26 tumors, but co-treatment with either LA or EA abrogated this effect. NS-positive CSCs were more abundant in CT26 tumors treated with 5-FU and either LA or EA compared with those treated with 5-FU alone. The results of the present study suggested that, rather than altering the sensitivity of cancer cells to 5-FU, LA and EA may promote the survival of CSCs. The results indicated that dietary composition during chemotherapy is an important issue.

Proton pump inhibitor induced collagen expression in colonocytes is associated with collagenous colitis.

AIM: To elucidate the role of proton pump inhibitors (PPIs) in collagenous disease, direct effect of PPI on colonocytes was examined. METHODS: Collagenous colitis is a common cause of non-bloody, watery diarrhea. Recently, there has been increasing focus on the use of proton PPIs as a risk factor for developing collagenous colitis. Mouse CT26 colonic cells were treated with PPI and/or PPI-induced alkaline media. Expression of fibrosis-associated genes was examined by RT-PCR. In human materials, collagen expression was examined by immunohistochemistry. RESULTS: CT26 cells expressed a Na+-H+ exchanger gene (solute carrier family 9, member A2). Treatment with PPI and/or PPI-induced alkaline media caused growth inhibition and oxidative stress in CT26 cells. The treatment increased expression of fibrosis inducing factors, transforming growth factor ß and fibroblast growth factor 2. The treatment also decreased expression of a negative regulator of collagen production, replication factor C1, resulting in increased expression of collagen types III and IV in association with lipid peroxide. In biopsy specimens from patients with collagenous colitis, type III and IV collagen were increased. Increase of type III collagen was more pronounced in PPI-associated collagenous colitis than in non-PPI-associated disease. CONCLUSION: From these findings, the reaction of colonocytes to PPI might participate in pathogenesis of collagenous colitis.