In our previous studies, we demonstrated that naturally occurring benzyl isothiocyanate (BITC) selectively suppress in vitro and in vivo growth of pancreatic cancer cells by inhibiting the phosphorylation (Tyr 705 and Ser 727) and constitutive expression of STAT-3 [JNCI, 101 (3), 2009]. In the present study, we investigated the effect of BITC on Janus Kinase (JAK) family of proteins, which are known to regulate STAT-3. Activation of JAKs has been reported in various tumor cells. Our results demonstrate that BITC treatment drastically decrease the constitutive expression as well as phosphorylation of JAK-3 at Tyr 980 in BxPC-3 human pancreatic cancer cells. However, phosphorylation of JAK1, JAK2 or Tyk2 was not suppressed by BITC treatment. In order to confirm the involvement of JAK-3, BxPC-3 cells were transfected with JAK-3 expressing plasmids and the transcriptional and DNA binding activity of STAT-3 was determined in the transfected cells after treatment with BITC. Inhibition of JAK-3 expression and phosphorylation by BITC treatment was almost completely abrogated in JAK-3 over expressing cells. The decrease in DNA binding and transcriptional activity of STAT-3 by BITC treatment was substantially attenuated in these cells. Moreover, cell cycle arrest and apoptosis inducing effect of BITC was also blocked. Similar observations were made in Capan-2 pancreatic cancer cells. Interestingly, BITC failed to cause any change in the expression of JAK-3 or STAT-3 in normal pancreatic epithelial cells. Our results thus demonstrate JAK-3 as an upstream regulator of STAT-3 and a critical molecular target of BITC in our model. These interesting findings provide a rationale for further preclinical and clinical investigation on the chemotherapeutic effects of BITC against pancreatic cancer. [Supported in part by RO1 grant CA 106953 (to SKS) awarded by National Cancer Institute].

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2971.

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

American Association for Cancer Research
2009