Lung cancer is the second leading cause of cancer related incidence and the leading cause of cancer-related mortality in the United States. Currently available therapies targeting lung cancer growth are largely ineffective and the 5 year survival of lung cancer patients remains dismal. Therefore, there is a need to develop new strategies based upon understanding and targeting the tumor microenvironment which play an important role in lung tumorigenesis. In last few years, the role of various cytokines has been shown in the interaction between lung cancer cells and its microenvironment cells. One of the important cytokines whose role has been reported in cell proliferation, apoptosis-evasion, promotion of angiogenesis, and invasion and metastasis of lung cancer cells is interleukin-1\#946;(IL-1\#946;). Earlier studies have also suggested the important role of iNOS in the inflammation, tumor angiogenesis, and growth and progression of lung cancer. Accordingly, in the present study we analyzed the mechanisms of IL-1\#946; (10 ng/mL)- mediated effects on iNOS expression at various time points (10, 20, 30, 60 and 180 minutes) in human lung epithelial carcinoma A549 cells. Our results show that IL-1\#946; treatment strongly induces the expression of iNOS after 30 minutes in serum starved A549 cells. Next, we assessed the effects of IL-1\#946; on various transcriptional factors which might be regulating the expression of iNOS in A549 cells. IL-1\#946; treatment resulted in a strong increase in the phosphorylation of STAT1 (Tyr701 and Ser727), STAT 3 (Tyr705 and Ser727) and NF-\#954;B p65 (Ser 536), and also increased the levels of HIF-1\#945; after 30 minutes treatment. Furthermore, IL-1\#946; increased the phosphorylation of Akt (Ser473) as well as those MAPK family members (ERK1/2, JNK1/2, and p38). In order to establish the role of these upstream signaling molecules in the IL-1\#946;-induced iNOS expression, we employed chemical inhibitors for JAK1 kinase (piceatannol; 50 µM), JAK2 kinase (AG 490; 50 µM), MEK1/2 (PD98059; 50 µM) and JNK1/2 (SP600025; 50 µM), and treated A549 cells with them individually for 2hrs before IL-1\#946; stimulation. The IL-1\#946;-induced iNOS expression was not inhibited in the presence of any of these inhibitors, suggesting that IL-1\#946;-induced iNOS expression does not depend on JAK-STAT and MAPKs activation. Further studies are underway to dissect the role of other important players in the regulation of iNOS expression by IL-1\#946; in A549 cells. Overall, the results of the present study suggest that novel inhibitors of IL-1\#946;-mediated signaling pathways should be developed which could target iNOS expression and regulation towards tumor microenvironment in lung cancer, thereby inhibiting the growth and progression of this most deadly human malignancy.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4428.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009