Identification of Novel Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors by Kinase Activity-Based High-Throughput Screening for Anticancer Therapeutics

Zhang, Wen; Hu, Xiaohui; Chakravarty, Harapriya; Zheng, Yang; Tam, Kin Yip

doi:10.1021/acscombsci.8b00104

Cited by 13 publications

(14 citation statements)

References 28 publications

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“…DCA and JX06 have been reported to reduce cancer growth through modulating metabolism and inducing apoptosis 36 , 38 . Recently, compound 10, a novel PDK inhibitor targeting lipoamide-binding pocket has successfully reduced the growth of several cancer cells 39 . In the present study, we could not precisely determine the in vitro inhibitory efficacy of HsA on the PDK1 activity.…”

Section: Discussionmentioning

confidence: 99%

Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity

Kim

Chung

Han

et al. 2020

Sci Rep

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Most cancer cells primarily produce their energy through a high rate of glycolysis followed by lactic acid fermentation even in the presence of abundant oxygen. Pyruvate dehydrogenase kinase (PDK) 1, an enzyme responsible for aerobic glycolysis via phosphorylating and inactivating pyruvate dehydrogenase (PDH) complex, is commonly overexpressed in tumors and recognized as a therapeutic target in colorectal cancer. Hemistepsin A (HsA) is a sesquiterpene lactone isolated from Hemistepta lyrata Bunge (Compositae). Here, we report that HsA is a PDK1 inhibitor can reduce the growth of colorectal cancer and consequent activation of mitochondrial ROS-dependent apoptotic pathway both in vivo and in vitro. Computational simulation and biochemical assays showed that HsA directly binds to the lipoamide-binding site of PDK1, and subsequently inhibits the interaction of PDK1 with the E2 subunit of PDH complex. As a result of PDK1 inhibition, lactate production was decreased, but oxygen consumption was increased. Mitochondrial ROS levels and mitochondrial damage were also increased. Consistent with these observations, the apoptosis of colorectal cancer cells was promoted by HsA with enhanced activation of caspase-3 and -9. These results suggested that HsA might be a potential candidate for developing a novel anti-cancer drug through suppressing cancer metabolism.

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Section: Discussionmentioning

confidence: 99%

Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity

Kim

Chung

Han

et al. 2020

Sci Rep

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“…The activation of oncogenes or the mutation of oncosuppressor genes, including p53, may be responsible of different deregulations leading to glycolytic metabolism and to the inhibition of the respiratory enzymes including cytochrome c oxidase. Previous work in our laboratory [ 33 , 85 , 86 ] demonstrated the overexpression of c- Myc, Cyclins D1, E , and A , and E2f1 genes, at mRNA and protein levels, and the increase of CDK4 (Cyclin-dependent kinase 4), Cyclin E-CDK2 (Cyclin-dependent kinase) and E2f1-DP1 complexes, and pRb hyperphosphorylation in dysplastic nodules and HCCs of the F344 rats, genetically susceptible to hepatocarcinogenesis. These changes were absent in the resistant BN rat lesions, in which Dusp1 (Dual Specificity Phosphatase 1) caused low Erk activation, whereas a Dusp1 decline, associated with high Erk activation, was found in the susceptible F344 (Fischer 344) rat lesions [ 86 ].…”

Section: The Genetic Susceptibility To Cancermentioning

confidence: 97%

“…The inactivation of PDK-1 was shown to decrease the lactate production in the head and neck squamous cancer cells [ 27 ]. Indeed, PDK-1 inhibits PDH [ 33 ] and consequently suppresses the transformation of pyruvate into acetyl-CoA, the Krebs cycle, and the reactions leading to the resynthesis of PEP and G6P.…”

Section: The Deregulation Of the Oxidative Metabolism In Cancermentioning

confidence: 99%

“…This is associated with HIF1α degradation, decrease of glycolysis, and thus the Warburg effect [ 156 , 157 ]. A contribution to the determination of the glycolytic metabolism of cancer cells is also given by the oncogene RAS through the increment of the expression of the glucose transporter GLUT1 (glucose transporter type 1) [ 158 ] and of key glycolytic enzymes such as enolase, PFK, and LDH [ 33 , 159 , 160 ] ( Figure 3 ).…”

Section: Cancer Cell Mitochondriamentioning

confidence: 99%

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The Warburg Effect 97 Years after Its Discovery

Pascale

Calvisi

Simile

et al. 2020

Cancers

211

128

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The deregulation of the oxidative metabolism in cancer, as shown by the increased aerobic glycolysis and impaired oxidative phosphorylation (Warburg effect), is coordinated by genetic changes leading to the activation of oncogenes and the loss of oncosuppressor genes. The understanding of the metabolic deregulation of cancer cells is necessary to prevent and cure cancer. In this review, we illustrate and comment the principal metabolic and molecular variations of cancer cells, involved in their anomalous behavior, that include modifications of oxidative metabolism, the activation of oncogenes that promote glycolysis and a decrease of oxygen consumption in cancer cells, the genetic susceptibility to cancer, the molecular correlations involved in the metabolic deregulation in cancer, the defective cancer mitochondria, the relationships between the Warburg effect and tumor therapy, and recent studies that reevaluate the Warburg effect. Taken together, these observations indicate that the Warburg effect is an epiphenomenon of the transformation process essential for the development of malignancy.

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“…It can increase the transcriptional activity of the androgen receptor by chemical mechanisms that include phosphorylation of Thr-360 and ubiquitination of Lys-240 and Lys-245 induced by the Epidermal Growth Factor. 20,21 Abnormally high quantities of MAGEA11 are associated with high expressions of the androgen receptor protein in prostate cancer. 22 The increased expression of MAGEA11 has a direct association with the progression of prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic T-lymphocyte elicited therapeutic vaccine candidate targeting cancer against MAGE-A11 carcinogenic protein

et al. 2020

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Immunotherapy is a breakthrough approach for cancer treatment and prevention. By exploiting the fact that cancer cells have overexpression of tumor antigens responsible for its growth and progression, which can be identified and removed by boosting the immune system. In silico techniques have provided efficient ways for developing preventive measures to ward off cancer. Herein, we have designed a potent cytotoxic T-lymphocyte epitope to elicit a desirable immune response against carcinogenic melanoma-associated antigen-A11. Potent epitope was predicted using reliable algorithms and characterized by advanced computational avenue CABS molecular dynamics simulation, for full flexible binding with HLA-A*0201 and androgen receptor to large-scale rearrangements of the complex system. Results showed the potent immunogenic construct (KIIDLVHLL), from top epitopes using five algorithms. Molecular docking analyses showed the strong binding of epitope with HLA-A*0201 and androgen receptor with docking score of -780.6 and -641.06 kcal/mol, respectively. Molecular dynamics simulation analysis revealed strong binding of lead epitope with androgen receptor by involvement of 127 elements through atomic-model study. Full flexibility study showed stable binding of epitope with an average RMSD 2.21 Å and maximum RMSD value of 6.48 Å in optimal cluster density area. The epitope also showed remarkable results with radius of gyration 23.0777 Å, world population coverage of 39.08% by immune epitope database, and TAP affinity IC50 value of 2039.65 nm. Moreover, in silico cloning approach confirmed the expression and translation capacity of the construct within a suitable expression vector. This study paves way for a potential immunogenic construct for prevention of cancer.

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Identification of Novel Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors by Kinase Activity-Based High-Throughput Screening for Anticancer Therapeutics

Cited by 13 publications

References 28 publications

Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity

Hemistepsin A suppresses colorectal cancer growth through inhibiting pyruvate dehydrogenase kinase activity

The Warburg Effect 97 Years after Its Discovery

Cytotoxic T-lymphocyte elicited therapeutic vaccine candidate targeting cancer against MAGE-A11 carcinogenic protein

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