Inhibition of JAK2/STAT3 signalling induces colorectal cancer cell apoptosis via mitochondrial pathway.
Bottom Line: In addition, our results demonstrated that the translocation of cytochrome c (Cyt c), caspase activation and cleavage of poly (ADP-ribose) polymerase (PARP) were present in apoptotic CRC cells after down-regulation of JAK2/STAT3 signalling.We found that JAK2/STAT3 target genes were decreased; meanwhile caspase cascade was activated in xenograft tumours.Therefore, JAK2/STAT3 signalling may be a potential target for therapy of CRC.
Affiliation: GI Division, Shanghai Jiao-Tong University School of Medicine Renji Hospital, Shanghai Institution of Digestive Disease, Key Laboratory of Gastroenterology & Hepatology, Shanghai, China.Show MeSH
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Mentions: Since the translocation of Cyt c can activate the caspase cascade , we further explored whether caspases were involved after inhibition of JAK2/STAT3 signalling. As illustrated in Figure 5A, pretreatment of CRC cells with AG490 decreased the expressions of pro-caspase9 and pro-caspase3, meanwhile increased the expression of cleaved-caspase9 and cleaved-caspase3. We also found that the most significant alteration emerged at 72 hrs after exposure to AG490. STAT3 siRNA induced similar effects. At 72 hrs after transfection with 100 nM of STAT3 siRNA, the expressions of pro-caspases3,9 of SW1116 and HT29 cells decreased and cleaved-caspases3,9 increased when compared with the equivalent transfection with nonspecific siRNA (Fig. 5B). However, the active caspase-8 involved in the death receptor pathway was not significantly increased, after transient transfection with STAT3 siRNA for 72 hrs in both CRC cell lines (Fig. S2). Our results suggested that the caspase cascade involved in the mitochondrial pathway is activated after inhibition of JAK2/STAT3 signalling.
Affiliation: GI Division, Shanghai Jiao-Tong University School of Medicine Renji Hospital, Shanghai Institution of Digestive Disease, Key Laboratory of Gastroenterology & Hepatology, Shanghai, China.