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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

Network-based identification of classical and novel apoptotic (kinase) pathways(A) The global PPI network in apoptosis. (B) Core apoptotic signaling subnetwork. (C) Predicted interactions amongst classical hub proteins in apoptosis. (D) Novel apoptotic kinase pathways involved in AMPK/ZIPK regulation in cancer.
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Figure 2: Network-based identification of classical and novel apoptotic (kinase) pathways(A) The global PPI network in apoptosis. (B) Core apoptotic signaling subnetwork. (C) Predicted interactions amongst classical hub proteins in apoptosis. (D) Novel apoptotic kinase pathways involved in AMPK/ZIPK regulation in cancer.

Mentions: Based upon some online databases, we computationally constructed the global PPI network. To construct the set of true-positive gene pairs, we manually derived physical PPIs. A total number of 85,083 unique PPIs among 13,128 proteins were prepared as data sources for our Golden Standard Positive (GSP) set. We generated a Golden Standard Negative (GSN) set that could be defined as all the possible pair-wise combinations, in which one protein is assigned to the plasma membrane and the other to the nucleus according to GO cellular component annotation, resulting in 23,169,177 pairs in our GSN (Table S1). Moreover, we integrated four different types of biological datasets and chose the likelihood ratio (LR) =117 as the reliability of individual dataset for inferring the apoptotic PPIs. Each dataset could be divided into several bins due to their intrinsic characters, and LR for each bin was calculated, indicating the corresponding results of cross-species interolog mapping (Figure 1A), gene co-expression profiles (Figure 1B), domain-domain interaction (DDI) (Figure 1C) and smallest shared biological process (SSBP) (Figure 1D), respectively. Subsequently, we used LR cutoff as 117 and achieved the global PPI network with 12,809 binary PPIs by combining the prediction set and the positive set (Figure 1E). Using the lunched Naïve Bayesian model, we found that STS containing 12,809 interacting protein pairs conformed by 4,818 unique proteins was input the network model, resulting the area under ROC curve (Figure 1F). As a result, we got the global PPI network, and further modified this network into the apoptotic PPI network (Figure 2A). We identified hub proteins implicated in core apoptotic pathways according to the four golden standards (the degree of each protein, the link number of apoptotic protein, network topology, and significance analysis of microarrays analysis). Thus, combination of the four standards that can be integrated into a well-suited approach to decrease the false-positive PPIs on some level; thereby, confirming apoptotic hub proteins (Figure S1).


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)

Network-based identification of classical and novel apoptotic (kinase) pathways(A) The global PPI network in apoptosis. (B) Core apoptotic signaling subnetwork. (C) Predicted interactions amongst classical hub proteins in apoptosis. (D) Novel apoptotic kinase pathways involved in AMPK/ZIPK regulation in cancer.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Network-based identification of classical and novel apoptotic (kinase) pathways(A) The global PPI network in apoptosis. (B) Core apoptotic signaling subnetwork. (C) Predicted interactions amongst classical hub proteins in apoptosis. (D) Novel apoptotic kinase pathways involved in AMPK/ZIPK regulation in cancer.
Mentions: Based upon some online databases, we computationally constructed the global PPI network. To construct the set of true-positive gene pairs, we manually derived physical PPIs. A total number of 85,083 unique PPIs among 13,128 proteins were prepared as data sources for our Golden Standard Positive (GSP) set. We generated a Golden Standard Negative (GSN) set that could be defined as all the possible pair-wise combinations, in which one protein is assigned to the plasma membrane and the other to the nucleus according to GO cellular component annotation, resulting in 23,169,177 pairs in our GSN (Table S1). Moreover, we integrated four different types of biological datasets and chose the likelihood ratio (LR) =117 as the reliability of individual dataset for inferring the apoptotic PPIs. Each dataset could be divided into several bins due to their intrinsic characters, and LR for each bin was calculated, indicating the corresponding results of cross-species interolog mapping (Figure 1A), gene co-expression profiles (Figure 1B), domain-domain interaction (DDI) (Figure 1C) and smallest shared biological process (SSBP) (Figure 1D), respectively. Subsequently, we used LR cutoff as 117 and achieved the global PPI network with 12,809 binary PPIs by combining the prediction set and the positive set (Figure 1E). Using the lunched Naïve Bayesian model, we found that STS containing 12,809 interacting protein pairs conformed by 4,818 unique proteins was input the network model, resulting the area under ROC curve (Figure 1F). As a result, we got the global PPI network, and further modified this network into the apoptotic PPI network (Figure 2A). We identified hub proteins implicated in core apoptotic pathways according to the four golden standards (the degree of each protein, the link number of apoptotic protein, network topology, and significance analysis of microarrays analysis). Thus, combination of the four standards that can be integrated into a well-suited approach to decrease the false-positive PPIs on some level; thereby, confirming apoptotic hub proteins (Figure S1).

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