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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

Proposed potential signaling pathway for the anisomycin-induced apoptosis in Jurkat T cells.The black lines or arrows display the literature-revealed signaling pathway, which is also proven strongly by our using anisomycin in the Jurkat T cell model, whereas the red lines or arrows show our result-revealed novel signaling connection.
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f8: Proposed potential signaling pathway for the anisomycin-induced apoptosis in Jurkat T cells.The black lines or arrows display the literature-revealed signaling pathway, which is also proven strongly by our using anisomycin in the Jurkat T cell model, whereas the red lines or arrows show our result-revealed novel signaling connection.

Mentions: Additionally, how does JNK impact the enhancement of Bim in the process of the anisomycin-induced apoptosis? A transcription factor AP-1 is a strong positive regulator of many miRNAs, including miR-21, miR-199a-5p and miR-203424344. We found that let-7c positively regulated both AP-1 and STAT1, but negatively did Bcl-xL in Jurkat T cells. Talotta et al. showed that miR-21 positively regulated the AP-1 activity by targeting its negative regulator PDCD4, suggesting that miR-21 is both the target and the regulator of AP-1 in the RAS-mediated transformation45. Our results reveal for the first time that let-7c may up-regulate the activities of both the AP-1 and the STAT1 to accelerate the phosphorylation of Bim, functioning as a bridge to pass JNK1/2 signaling onto the AP-1/STAT1/STAT3, thereby activating the AP-1/STAT1, and inhibiting the STAT3. It has been reported that AP-1/STAT1 can augment the Bim level, whereas let-7c directly diminishes the level of STAT3. Moreover, the current study indicates that let-7c is able to attenuate the Bcl-xL level through decreasing STAT3 activity. Furthermore, Bim can activate Bax and Bak, thereby initiating the cell apoptosis (Fig. 8). Therefore, we can conclude that the miRNA let-7c links the JNK1/2 to the AP-1/STAT1/STAT3 signaling, and activates the Bak/Bax through breaking the balance between the anti-apoptotic Bcl-2 family protein and the proapoptotic BH3-Only protein, finally resulting in the anisomycin-triggered apoptosis of Jurkat T cells. This provides a novel insight into the mechanisms by which anisomycin causes the apoptosis of the cancer cells. Considering its low dose and high efficacy as well as the low adverse effect profile, anisomycin is relatively promising to be developed and potentially applied to the clinical treatment of the human acute lymphocyte leukemia.


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)

Proposed potential signaling pathway for the anisomycin-induced apoptosis in Jurkat T cells.The black lines or arrows display the literature-revealed signaling pathway, which is also proven strongly by our using anisomycin in the Jurkat T cell model, whereas the red lines or arrows show our result-revealed novel signaling connection.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834478&req=5

f8: Proposed potential signaling pathway for the anisomycin-induced apoptosis in Jurkat T cells.The black lines or arrows display the literature-revealed signaling pathway, which is also proven strongly by our using anisomycin in the Jurkat T cell model, whereas the red lines or arrows show our result-revealed novel signaling connection.
Mentions: Additionally, how does JNK impact the enhancement of Bim in the process of the anisomycin-induced apoptosis? A transcription factor AP-1 is a strong positive regulator of many miRNAs, including miR-21, miR-199a-5p and miR-203424344. We found that let-7c positively regulated both AP-1 and STAT1, but negatively did Bcl-xL in Jurkat T cells. Talotta et al. showed that miR-21 positively regulated the AP-1 activity by targeting its negative regulator PDCD4, suggesting that miR-21 is both the target and the regulator of AP-1 in the RAS-mediated transformation45. Our results reveal for the first time that let-7c may up-regulate the activities of both the AP-1 and the STAT1 to accelerate the phosphorylation of Bim, functioning as a bridge to pass JNK1/2 signaling onto the AP-1/STAT1/STAT3, thereby activating the AP-1/STAT1, and inhibiting the STAT3. It has been reported that AP-1/STAT1 can augment the Bim level, whereas let-7c directly diminishes the level of STAT3. Moreover, the current study indicates that let-7c is able to attenuate the Bcl-xL level through decreasing STAT3 activity. Furthermore, Bim can activate Bax and Bak, thereby initiating the cell apoptosis (Fig. 8). Therefore, we can conclude that the miRNA let-7c links the JNK1/2 to the AP-1/STAT1/STAT3 signaling, and activates the Bak/Bax through breaking the balance between the anti-apoptotic Bcl-2 family protein and the proapoptotic BH3-Only protein, finally resulting in the anisomycin-triggered apoptosis of Jurkat T cells. This provides a novel insight into the mechanisms by which anisomycin causes the apoptosis of the cancer cells. Considering its low dose and high efficacy as well as the low adverse effect profile, anisomycin is relatively promising to be developed and potentially applied to the clinical treatment of the human acute lymphocyte leukemia.

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