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microRNA let-7c is essential for the anisomycin-elicited apoptosis in Jurkat T cells by linking JNK1/2 to AP-1/STAT1/STAT3 signaling.

Zhou Z, Lu X, Wang J, Xiao J, Liu J, Xing F - Sci Rep (2016)

Bottom Line: The results showed that anisomycin sufficiently promoted the apoptosis in human leukemic Jurkat T cells at a quite low dose. microRNA let-7c (let-7c) contributed to the anisomycin-induced apoptosis, which could be abrogated by the inactivation of JNK signaling.The let-7c deficiency reduced the AP-1, STAT1 and Bim activities, and enhanced the STAT3 and Bcl-xL, alleviating the anisomycin-induced apoptosis.This provides a novel insight into the mechanism by which anisomycin leads to the tumor cell apoptosis, potentially laying the foundations for its development and clinical application.

View Article: PubMed Central - PubMed

Affiliation: Institute of Tissue Transplantation and Immunology, Department of Immunobiology, Jinan University, Guangzhou 510632, China.

ABSTRACT
Anisomycin, an antibiotic produced by Streptomyces griseolus, strongly induces apoptosis in various tumor cells in vitro, superior dramatically to adriamycin. The present study aims to elucidate its detailed mechanistic process. The results showed that anisomycin sufficiently promoted the apoptosis in human leukemic Jurkat T cells at a quite low dose. microRNA let-7c (let-7c) contributed to the anisomycin-induced apoptosis, which could be abrogated by the inactivation of JNK signaling. The let-7c over-expression and the addition of its mimics facilitated the activation of AP-1, STAT1 and Bim by linking JNK1/2 to AP-1/STAT1, but rather inhibited the activation of STAT3 and Bcl-xL by connecting JNK1/2 to STAT3, followed by the augmented apoptosis in the cells. The let-7c deficiency reduced the AP-1, STAT1 and Bim activities, and enhanced the STAT3 and Bcl-xL, alleviating the anisomycin-induced apoptosis. The knockdown of the bim gene repressed the anisomycin-boosted apoptosis through the attenuation of the active Bak and Bax. The findings indicate for the first time that miR let-7c is essential for the anisomycin-triggered apoptosis by linking JNK1/2 to AP-1/STAT1/STAT3/Bim/Bcl-xL/Bax/Bak signaling. This provides a novel insight into the mechanism by which anisomycin leads to the tumor cell apoptosis, potentially laying the foundations for its development and clinical application.

No MeSH data available.


Related in: MedlinePlus

Anisomycin promoted the apoptosis of Jurkat T cells through the JNK-dependent activation of Bim/Bcl-xL.Jurkat T cells were pre-incubated with 10 μM SP600125 (SP), 20 μM PD98059 (PD) or the increasing concentrations of SP600125 for 2 h before treated with the indicated concentrations of anisomycin (Ani) for 6 h. Additionally, the cells were treated with 40 ng/ml of anisomycin at the indicated time points. (A–G) The expression levels of P-Bim and P-Bcl-xL were assessed by Western blot analysis. (H,I) The alterations of Bim and Bcl-xL mRNAs were evaluated by RT-PCR. (J) Furthermore, Bim-targeting siRNA was used to knock down the bim gene to confirm the correlation of its mRNA and protein levels with the cell apoptosis. Data are presented as the mean ± SD of three independent experiments for (A–I). *P < 0.05, ** P < 0.01 vs. the untreated control, #P < 0.05, ##P < 0.01 vs. the 40 ng/ml of anisomycin alone.
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f3: Anisomycin promoted the apoptosis of Jurkat T cells through the JNK-dependent activation of Bim/Bcl-xL.Jurkat T cells were pre-incubated with 10 μM SP600125 (SP), 20 μM PD98059 (PD) or the increasing concentrations of SP600125 for 2 h before treated with the indicated concentrations of anisomycin (Ani) for 6 h. Additionally, the cells were treated with 40 ng/ml of anisomycin at the indicated time points. (A–G) The expression levels of P-Bim and P-Bcl-xL were assessed by Western blot analysis. (H,I) The alterations of Bim and Bcl-xL mRNAs were evaluated by RT-PCR. (J) Furthermore, Bim-targeting siRNA was used to knock down the bim gene to confirm the correlation of its mRNA and protein levels with the cell apoptosis. Data are presented as the mean ± SD of three independent experiments for (A–I). *P < 0.05, ** P < 0.01 vs. the untreated control, #P < 0.05, ##P < 0.01 vs. the 40 ng/ml of anisomycin alone.

Mentions: As shown in Fig. 3A–C, the expressions of both P-Bcl-xl and P-Bim proteins were significantly up-regulated with the enhancing concentrations of anisomycin, presenting a dose- or time-related relationship. These changes could be reversed by SP600125, nor PD98059 (Fig. 3B,D–G). Moreover, the expressions of both the P-Bcl-xl and P-Bim proteins induced by anisomycin were obviously down-regulated with the increasing concentrations of SP600125 in a dose-dependent manner (Fig. 3F,G). The Bim mRNA expression was significantly increased with the increasing concentrations of anisomycin in a dose-dependent manner, whereas the Bcl-xL mRNA was obviously decreased with the incremental anisomycin concentrations in a dose-dependent manner (Fig. 3H,I). When the bim gene was knocked down with the Bim-targeting siRNA, the process of the anisomycin-induced cell apoptosis might be blocked, following the reduction of Bim mRNA and protein (Fig. 3J). These results strongly indicate that the anisomycin-promoted apoptosis in Jurkat T cells through the JNK-dependent activation of Bim/Bcl-xL.


microRNA let-7c is essential for the anisomycin-elicited apoptosis in Jurkat T cells by linking JNK1/2 to AP-1/STAT1/STAT3 signaling.

Zhou Z, Lu X, Wang J, Xiao J, Liu J, Xing F - Sci Rep (2016)

Anisomycin promoted the apoptosis of Jurkat T cells through the JNK-dependent activation of Bim/Bcl-xL.Jurkat T cells were pre-incubated with 10 μM SP600125 (SP), 20 μM PD98059 (PD) or the increasing concentrations of SP600125 for 2 h before treated with the indicated concentrations of anisomycin (Ani) for 6 h. Additionally, the cells were treated with 40 ng/ml of anisomycin at the indicated time points. (A–G) The expression levels of P-Bim and P-Bcl-xL were assessed by Western blot analysis. (H,I) The alterations of Bim and Bcl-xL mRNAs were evaluated by RT-PCR. (J) Furthermore, Bim-targeting siRNA was used to knock down the bim gene to confirm the correlation of its mRNA and protein levels with the cell apoptosis. Data are presented as the mean ± SD of three independent experiments for (A–I). *P < 0.05, ** P < 0.01 vs. the untreated control, #P < 0.05, ##P < 0.01 vs. the 40 ng/ml of anisomycin alone.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4834478&req=5

f3: Anisomycin promoted the apoptosis of Jurkat T cells through the JNK-dependent activation of Bim/Bcl-xL.Jurkat T cells were pre-incubated with 10 μM SP600125 (SP), 20 μM PD98059 (PD) or the increasing concentrations of SP600125 for 2 h before treated with the indicated concentrations of anisomycin (Ani) for 6 h. Additionally, the cells were treated with 40 ng/ml of anisomycin at the indicated time points. (A–G) The expression levels of P-Bim and P-Bcl-xL were assessed by Western blot analysis. (H,I) The alterations of Bim and Bcl-xL mRNAs were evaluated by RT-PCR. (J) Furthermore, Bim-targeting siRNA was used to knock down the bim gene to confirm the correlation of its mRNA and protein levels with the cell apoptosis. Data are presented as the mean ± SD of three independent experiments for (A–I). *P < 0.05, ** P < 0.01 vs. the untreated control, #P < 0.05, ##P < 0.01 vs. the 40 ng/ml of anisomycin alone.
Mentions: As shown in Fig. 3A–C, the expressions of both P-Bcl-xl and P-Bim proteins were significantly up-regulated with the enhancing concentrations of anisomycin, presenting a dose- or time-related relationship. These changes could be reversed by SP600125, nor PD98059 (Fig. 3B,D–G). Moreover, the expressions of both the P-Bcl-xl and P-Bim proteins induced by anisomycin were obviously down-regulated with the increasing concentrations of SP600125 in a dose-dependent manner (Fig. 3F,G). The Bim mRNA expression was significantly increased with the increasing concentrations of anisomycin in a dose-dependent manner, whereas the Bcl-xL mRNA was obviously decreased with the incremental anisomycin concentrations in a dose-dependent manner (Fig. 3H,I). When the bim gene was knocked down with the Bim-targeting siRNA, the process of the anisomycin-induced cell apoptosis might be blocked, following the reduction of Bim mRNA and protein (Fig. 3J). These results strongly indicate that the anisomycin-promoted apoptosis in Jurkat T cells through the JNK-dependent activation of Bim/Bcl-xL.

Bottom Line: The results showed that anisomycin sufficiently promoted the apoptosis in human leukemic Jurkat T cells at a quite low dose. microRNA let-7c (let-7c) contributed to the anisomycin-induced apoptosis, which could be abrogated by the inactivation of JNK signaling.The let-7c deficiency reduced the AP-1, STAT1 and Bim activities, and enhanced the STAT3 and Bcl-xL, alleviating the anisomycin-induced apoptosis.This provides a novel insight into the mechanism by which anisomycin leads to the tumor cell apoptosis, potentially laying the foundations for its development and clinical application.

View Article: PubMed Central - PubMed

Affiliation: Institute of Tissue Transplantation and Immunology, Department of Immunobiology, Jinan University, Guangzhou 510632, China.

ABSTRACT
Anisomycin, an antibiotic produced by Streptomyces griseolus, strongly induces apoptosis in various tumor cells in vitro, superior dramatically to adriamycin. The present study aims to elucidate its detailed mechanistic process. The results showed that anisomycin sufficiently promoted the apoptosis in human leukemic Jurkat T cells at a quite low dose. microRNA let-7c (let-7c) contributed to the anisomycin-induced apoptosis, which could be abrogated by the inactivation of JNK signaling. The let-7c over-expression and the addition of its mimics facilitated the activation of AP-1, STAT1 and Bim by linking JNK1/2 to AP-1/STAT1, but rather inhibited the activation of STAT3 and Bcl-xL by connecting JNK1/2 to STAT3, followed by the augmented apoptosis in the cells. The let-7c deficiency reduced the AP-1, STAT1 and Bim activities, and enhanced the STAT3 and Bcl-xL, alleviating the anisomycin-induced apoptosis. The knockdown of the bim gene repressed the anisomycin-boosted apoptosis through the attenuation of the active Bak and Bax. The findings indicate for the first time that miR let-7c is essential for the anisomycin-triggered apoptosis by linking JNK1/2 to AP-1/STAT1/STAT3/Bim/Bcl-xL/Bax/Bak signaling. This provides a novel insight into the mechanism by which anisomycin leads to the tumor cell apoptosis, potentially laying the foundations for its development and clinical application.

No MeSH data available.


Related in: MedlinePlus