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Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer.

Fu L, Zhang S, Zhang L, Tong X, Zhang J, Zhang Y, Ouyang L, Liu B, Huang J - Oncotarget (2015)

Bottom Line: Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008).Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK.Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

ABSTRACT
The aim of this study was to discover a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. In this study, we systematically constructed the global protein-protein interaction (PPI) network and predicted apoptosis-related protein connections by the Naïve Bayesian model. Then, we identified some classical apoptotic PPIs and other previously unrecognized PPIs between apoptotic kinases, such as AMPK and ZIPK. Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008). Moreover, we found BL-AD008 bear remarkable anti-proliferative activities toward cervical cancer cells and could induce apoptosis by death-receptor and mitochondrial pathways. Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK. Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo. In conclusion, these results demonstrate the ability of systems biology network to identify some key apoptotic kinase targets AMPK and ZIPK; thus providing a dual-target small molecule activator (BL-AD008) as a potential new apoptosis-modulating drug in future cervical cancer therapy.

No MeSH data available.


Related in: MedlinePlus

BL-AD008 induces apoptosis by targeting AMPK and ZIPK(A) BL-AD008-induced apoptosis is partly dependent on ZIPK. (B) BL-AD008-induced apoptosis is partly dependent on AMPK. (A) BL-AD008-induced apoptosis is mainly dependent on ZIPK and AMPK.
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Figure 7: BL-AD008 induces apoptosis by targeting AMPK and ZIPK(A) BL-AD008-induced apoptosis is partly dependent on ZIPK. (B) BL-AD008-induced apoptosis is partly dependent on AMPK. (A) BL-AD008-induced apoptosis is mainly dependent on ZIPK and AMPK.

Mentions: To examine whether BL-AD008 is targeted AMPK/ZIPK activator, we showed that AMPK expression was remarkably decreased in BL-AD008+AMPK siRNA-treated HeLa cells compared with BL-AD008-indcued HeLa cells. In addition, we examined the expressions of caspase-8, caspase-9 and caspase-3 between BL-AD008-treated and BL-AD008+AMPK siRNA-treated conditions. Caspase-8, caspase-9 and caspase-3 expressions were partially decreased in BL-AD008+AMPK siRNA-treated than BL-AD008-treated HeLa cells. It suggests that AMPK activation may have more effects on the activation of caspase-8, caspase-9 and caspase-3 in BL-AD008-induced apoptosis (Figure 7A).


Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer.

Fu L, Zhang S, Zhang L, Tong X, Zhang J, Zhang Y, Ouyang L, Liu B, Huang J - Oncotarget (2015)

BL-AD008 induces apoptosis by targeting AMPK and ZIPK(A) BL-AD008-induced apoptosis is partly dependent on ZIPK. (B) BL-AD008-induced apoptosis is partly dependent on AMPK. (A) BL-AD008-induced apoptosis is mainly dependent on ZIPK and AMPK.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480736&req=5

Figure 7: BL-AD008 induces apoptosis by targeting AMPK and ZIPK(A) BL-AD008-induced apoptosis is partly dependent on ZIPK. (B) BL-AD008-induced apoptosis is partly dependent on AMPK. (A) BL-AD008-induced apoptosis is mainly dependent on ZIPK and AMPK.
Mentions: To examine whether BL-AD008 is targeted AMPK/ZIPK activator, we showed that AMPK expression was remarkably decreased in BL-AD008+AMPK siRNA-treated HeLa cells compared with BL-AD008-indcued HeLa cells. In addition, we examined the expressions of caspase-8, caspase-9 and caspase-3 between BL-AD008-treated and BL-AD008+AMPK siRNA-treated conditions. Caspase-8, caspase-9 and caspase-3 expressions were partially decreased in BL-AD008+AMPK siRNA-treated than BL-AD008-treated HeLa cells. It suggests that AMPK activation may have more effects on the activation of caspase-8, caspase-9 and caspase-3 in BL-AD008-induced apoptosis (Figure 7A).

Bottom Line: Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008).Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK.Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

ABSTRACT
The aim of this study was to discover a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. In this study, we systematically constructed the global protein-protein interaction (PPI) network and predicted apoptosis-related protein connections by the Naïve Bayesian model. Then, we identified some classical apoptotic PPIs and other previously unrecognized PPIs between apoptotic kinases, such as AMPK and ZIPK. Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008). Moreover, we found BL-AD008 bear remarkable anti-proliferative activities toward cervical cancer cells and could induce apoptosis by death-receptor and mitochondrial pathways. Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK. Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo. In conclusion, these results demonstrate the ability of systems biology network to identify some key apoptotic kinase targets AMPK and ZIPK; thus providing a dual-target small molecule activator (BL-AD008) as a potential new apoptosis-modulating drug in future cervical cancer therapy.

No MeSH data available.


Related in: MedlinePlus