TY - JOUR
T1 - Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines
T2 - Inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells
AU - Lin, Quan
AU - Lai, Raymond
AU - Chirieac, Lucian R.
AU - Li, Changping
AU - Thomazy, Vilmos A.
AU - Grammatikakis, Ioannis
AU - Rassidakis, George Z.
AU - Zhang, Wei
AU - Fujio, Yasushi
AU - Kunisada, Keita
AU - Hamilton, Stanley R.
AU - Amin, Hesham M.
N1 - Funding Information:
Supported by a Career Development Award from the National Institutes of Health Specialized Programs of Research Excellence grant to MD Anderson Cancer Center (H.M.A.) and H.M.A. is a scholar of the Physician Scientist Program at MD Anderson Cancer Center.
PY - 2005/10
Y1 - 2005/10
N2 - 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-XL, Mcl-1, and cyclin D2 and up-regulation of p21 waf1/ciP1 and p27kip1. 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.
AB - 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-XL, Mcl-1, and cyclin D2 and up-regulation of p21 waf1/ciP1 and p27kip1. 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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U2 - 10.1016/S0002-9440(10)61187-X
DO - 10.1016/S0002-9440(10)61187-X
M3 - Article
C2 - 16192633
AN - SCOPUS:26244463218
SN - 0002-9440
VL - 167
SP - 969
EP - 980
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -