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(American Journal of Pathology. 2005;167:969-980.)
© 2005 American Society for Investigative Pathology

Constitutive Activation of JAK3/STAT3 in Colon Carcinoma Tumors and Cell Lines

Inhibition of JAK3/STAT3 Signaling Induces Apoptosis and Cell Cycle Arrest of Colon Carcinoma Cells

Quan Lin^*, Raymond Lai, Lucian R. Chirieac^*, Changping Li^*, Vilmos A. Thomazy^*, Ioannis Grammatikakis^*, George Z. Rassidakis^*, Wei Zhang^*, Yasushi Fujio, Keita Kunisada, Stanley R. Hamilton^* and Hesham M. Amin^*

From the Division of Pathology and Laboratory Medicine,^* The University of Texas MD Anderson Cancer Center, Houston, Texas; the Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada; and the Department of Molecular Medicine, Graduate School of Medicine, Osaka, Japan

Signal transducer and activator of transcription 3 (STAT3) has oncogenic potential. The biological effects of STAT3 have not been studied extensively in the pathogenesis of colon cancer, nor has the role of Janus kinase 3 (JAK3), the physiological activator of STAT3, been evaluated. Here, we demonstrate that activated STAT3 (pSTAT3) and activated JAK3 (pJAK3) are expressed constitutively in two colon cancer cell lines, SW480 and HT29. To evaluate the significance of JAK3/STAT3 signaling, we inhibited JAK3 with AG490 and STAT3 with a dominant-negative construct. Inhibition of JAK3 down-regulated pSTAT3. The blockade of JAK3/STAT3 signaling significantly decreased viability of colon cancer cells due to apoptosis and cell-cycle arrest through down-regulation of Bcl-2, Bcl-X_L, Mcl-1, and cyclin D2 and up-regulation of p21^waf1/cip1 and p27^kip1. We also examined histological sections from 22 tumors from patients with stage II or stage IV colon cancer and found STAT3, JAK3, and their activated forms to be frequently expressed. Furthermore, quantitative reverse transcriptase-polymerase chain reaction identified JAK3 mRNA in colon cancer cell lines and primary tumors. Our findings illustrate the biological importance of JAK3/STAT3 activation in the oncogenesis of colon cancer and provide novel evidence that JAK3 is expressed and contributes to STAT3 activation in this malignant neoplasm.

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