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.
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.
Lin
Quan
Q
Division of Pathology and Laboratory Medicine, Box 72, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Lai
Raymond
R
Chirieac
Lucian R
LR
Li
Changping
C
Thomazy
Vilmos A
VA
Grammatikakis
Ioannis
I
Rassidakis
George Z
GZ
Zhang
Wei
W
Fujio
Yasushi
Y
Kunisada
Keita
K
Hamilton
Stanley R
SR
Amin
Hesham M
HM
D000368:Aged; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056742:Cyclin D2; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D053616:Janus Kinase 3; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
C080336:CCND2 protein, human; C493956:CDKN1A protein, human; D056742:Cyclin D2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3