Janus-activated kinases and signal transducer and activator of transcription control tumor growth response to camptothecin in human colon cancer cells.
Activation of Janus kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs) plays a crucial role in cell survival and proliferation. The JAK/STAT signaling pathway has received a great deal of attention as a therapeutic target for the treatment of cancer. Thus, the identification of a compound that blocks this pathway would contribute significantly to growth inhibition and apoptosis of tumor cells. The antitumor alkaloid camptothecin (CPT) may be useful in the treatment of certain cancer, but the effects of this drug on colon cancer cells remain largely undefined. The purpose of the present study was to characterize the effects of CPT on human colon cancer cells and to determine the cellular mechanisms involved in CPT-mediated cell inhibition. The cellular determinants for CPT activity were studied in six colon cancer cell lines; these cell lines exhibited natural differences in sensitivity to CPT and could be ranked according to increasing resistance levels in the order Lovo < SW48 < HCT116 < HCT8 < HT29 < WiDr. Our findings suggest that JAK2 is necessary for induction of apoptosis following CPT treatment. Inhibition of JAK2 and STAT3 Tyr705 phosphorylation decreased the expression of STAT3 downstream target genes such as Bcl-2, Bcl-x(L) and Mcl-1. Finally, we show that JAK2 mRNA expression to be a better determination for CPT sensitivity than the topoisomerase-I activity or mRNA expression.
Yun
Hyun Jin
HJ
Korea Institute of Radiological & Medical Sciences, Seoul, Korea.
Kim
Sun Young
SY
Kwon
Young Yon
YY
Kim
Chun-Ho
CH
Kang
Chang-Mo
CM
Kim
Eun Ju
EJ
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002166:Camptothecin / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D004260:DNA Repair / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D053614:Janus Kinase 2; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin