Alpha linolenic acid inhibits human renal cell carcinoma cell proliferation through PPARy activation and COX2 inhibition

n3 fatty acids have potential anticancer effects, and consuming food rich in n3 fatty acids reduces the human renal cell carcinoma (RCC) risk. However, the direct effect of n3 fatty acids on RCC in vitro is unknown. In the present study, the effects of alpha linolenic acid (ALA), an n3 fatty acid, were observed on cell proliferation in the RCC cell line OS  RC  2. The activity and gene expression levels of peroxisome proliferators activated receptor gamma  (PPARg) and cyclooxygenase 2 (COX 2) in the OS RC 2 cells were measured by ELISA and real time R PCR, respectively, following ALA treatment. ALA (20 to 80 microM) dose dependently suppressed the proliferation of the OS RC 2 cells. PPARg activity and gene expression were significantly increased by ALA at 20 and 40 microM. COX  2 activity and gene expression levels were significantly decreased by ALA from 20 microM. Use of purely the PPARg agonist, rosiglitazone, decreased the proliferation of the OS RC 2 cells, while ALA induced further suppression of cell proliferation in the presence of rosiglitazone. The COX 2 inhibitor N (3 Pyridyl)indomethacinamide induced further suppression of cell proliferation in the presence of rosiglitazone. N(3 Pyridyl)indomethacinamide also suppressed the proliferation of the OS RC2 cells. In the presence of N(3 Pyridyl)indomethacinamide, ALA and rosiglitazone further inhibited OS RC 2 cell proliferation. In conclusion, ALA inhibits the cell proliferation of the OS RC 2 human RCC cell line. PPARg activation and COX 2 inhibition serve as two signaling pathways for the inhibitory effects of ALA on RCC cell proliferation. (Authors abstract)
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and the most lethal of all genitourinary tumors. The majority of RCCs are resistant to radiation therapy and chemotherapy. Current research is focusing on the development of new methods for RCC therapy. The dietary intake of n3 fatty acids is associated with a reduced risk of certain types of cancer in human populations and animal models. The anticancer effects of n3 fatty acids may be mediated by multiple pathways, including peroxisome proliferatoractivated receptor gamma (PPARg) activation implicated in the pathology of numerous diseases, including obesity and diabetes. Fatty acids may activate PPARg then inhibit the growth of cancer cells. However, its role in RCC growth has not been clarified.

Cyclooxygenase  2 (COX  2) has also been suggested to be involved in the development of cancers. COX  2 is an inducible enzyme involved in inflammatory processes. Increasing evidence indicates that COX  2 inhibition has an important role in the prevention of cancer and in the delay of progression in established cancer. For example, ω  3 fatty acids have been shown to downregulate COX  2 expression and inhibit hepatocellular carcinoma cell growth. It has been observed that COX  2 is highly expressed in RCC tissues and that it shows a correlation with pathological features and prognosis in patients with RCC . The role of COX 2 in the development of RCC is not fully understood. In the present study, the effects of ALA on the proliferation of human RCC cell line OS  RC  2 cells were observed in vitro, and the involvement of PPAR  γ and COX  2 was demonstrated in the effects of ALA.
The present study demonstrated that ALA inhibited the proliferation of human RCC cells in vitro, and that PPARg activation is a signaling pathway that is involved in the action of ALA on OS RC 2 RCC cells. PPARg is a transcriptional factor that regulates metabolism and numerous other cell functions. PPARg activity and gene expression were markedly increased by ALA. Furthermore, it was observed that the PPARg agonist inhibited the proliferation of the OS RC 2 cells. The activation of PPARg by ALA is one of the signaling pathways for the inhibition of OS RC 2 cell proliferation.  In combination with the PPARg agonist, ALA further inhibited cell proliferation, indicating that other mechanism besides PPARg were also involved in the action of ALA. The present study clarified that COX 2 inhibition is another mechanism for the inhibition of OS RC 2 cell proliferation by ALA. COX 2 activity and gene expression were suppressed following ALA treatment. The results showed that the COX 2 inhibitor significantly inhibited OS RC 2 cell proliferation. Therefore, it was demonstrated that COX 2 inhibition led to decreases in OS RC 2 cell proliferation. ALA inhibits COX 2 activity, resulting in the inhibition of cell proliferation. Therefore, COX 2 inhibition is considered to be another signaling pathway through which ALA inhibits RCC cell proliferation.
It is suggested that PPARg activation and COX 2 inhibition serve as two signaling pathways for the inhibitory effects of ALA in RCC cell proliferation, and that these two signaling pathways are parallel in the route map. In the present study, following PPARg activation, the COX 2 inhibitor further suppressed the proliferation of the OS RC 2 cells in addition to PPARg activation.   In conclusion, the present study demonstrated that ALA inhibited the proliferation of OS RC 2 cells, a type of human RCC cell line. PPARg activation and COX 2 inhibition are two signaling pathways involved in the action of ALA on OS RC 2 cells.  ALA and drugs regulating the activities of PPARg and COX 2 may be potential targets for RCC therapy. (Editors comments)