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Inhibition of JAK2/STAT3 signalling induces colorectal cancer cell apoptosis via mitochondrial pathway.

Du W, Hong J, Wang YC, Zhang YJ, Wang P, Su WY, Lin YW, Lu R, Zou WP, Xiong H, Fang JY - J. Cell. Mol. Med. (2012)

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.Our findings illustrated the biological significance of JAK2/STAT3 signalling in CRC apoptosis, and provided novel evidence that inhibition of JAK2/STAT3 induced apoptosis via the mitochondrial apoptotic pathway.Therefore, JAK2/STAT3 signalling may be a potential target for therapy of CRC.

View Article: PubMed Central - PubMed

Affiliation: GI Division, Shanghai Jiao-Tong University School of Medicine Renji Hospital, Shanghai Institution of Digestive Disease, Key Laboratory of Gastroenterology & Hepatology, Shanghai, China.

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Disruption of JAK2/STAT3 signalling induces caspase-dependent apoptosis in CRC cells. (A) Pro-caspase9 and pro-caspase3 decreased, while cleaved-caspase9 and cleaved-caspase3 increased after treatment with AG490 in a time-dependent manner. (B) A similar pattern of changes was identified after transfection with STAT3 siRNA. (C) PARP was cleaved in a time-dependent manner after AG490 treatment and pro-PARP was reduced simultaneously. (D) Effects of STAT3 siRNA on the cleavage of PARP. At 48 hrs post-transfection, pro-PARP expression was down-regulated and cleaved-PARP up-regulated compared to that of negative control.
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fig05: Disruption of JAK2/STAT3 signalling induces caspase-dependent apoptosis in CRC cells. (A) Pro-caspase9 and pro-caspase3 decreased, while cleaved-caspase9 and cleaved-caspase3 increased after treatment with AG490 in a time-dependent manner. (B) A similar pattern of changes was identified after transfection with STAT3 siRNA. (C) PARP was cleaved in a time-dependent manner after AG490 treatment and pro-PARP was reduced simultaneously. (D) Effects of STAT3 siRNA on the cleavage of PARP. At 48 hrs post-transfection, pro-PARP expression was down-regulated and cleaved-PARP up-regulated compared to that of negative control.

Mentions: Since the translocation of Cyt c can activate the caspase cascade [25], 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.


Inhibition of JAK2/STAT3 signalling induces colorectal cancer cell apoptosis via mitochondrial pathway.

Du W, Hong J, Wang YC, Zhang YJ, Wang P, Su WY, Lin YW, Lu R, Zou WP, Xiong H, Fang JY - J. Cell. Mol. Med. (2012)

Disruption of JAK2/STAT3 signalling induces caspase-dependent apoptosis in CRC cells. (A) Pro-caspase9 and pro-caspase3 decreased, while cleaved-caspase9 and cleaved-caspase3 increased after treatment with AG490 in a time-dependent manner. (B) A similar pattern of changes was identified after transfection with STAT3 siRNA. (C) PARP was cleaved in a time-dependent manner after AG490 treatment and pro-PARP was reduced simultaneously. (D) Effects of STAT3 siRNA on the cleavage of PARP. At 48 hrs post-transfection, pro-PARP expression was down-regulated and cleaved-PARP up-regulated compared to that of negative control.
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Related In: Results  -  Collection

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fig05: Disruption of JAK2/STAT3 signalling induces caspase-dependent apoptosis in CRC cells. (A) Pro-caspase9 and pro-caspase3 decreased, while cleaved-caspase9 and cleaved-caspase3 increased after treatment with AG490 in a time-dependent manner. (B) A similar pattern of changes was identified after transfection with STAT3 siRNA. (C) PARP was cleaved in a time-dependent manner after AG490 treatment and pro-PARP was reduced simultaneously. (D) Effects of STAT3 siRNA on the cleavage of PARP. At 48 hrs post-transfection, pro-PARP expression was down-regulated and cleaved-PARP up-regulated compared to that of negative control.
Mentions: Since the translocation of Cyt c can activate the caspase cascade [25], 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.

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.Our findings illustrated the biological significance of JAK2/STAT3 signalling in CRC apoptosis, and provided novel evidence that inhibition of JAK2/STAT3 induced apoptosis via the mitochondrial apoptotic pathway.Therefore, JAK2/STAT3 signalling may be a potential target for therapy of CRC.

View Article: PubMed Central - PubMed

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
Related in: MedlinePlus