Janus-activated kinases and signal transducer and activator of transcription control tumor growth response to camptothecin in human colon cancer cells.

ABSTRACT

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.