Identification of pyruvate dehydrogenase kinase 1 inhibitors with anti-osteosarcoma activity

Fang, Aiping; Luo, Huiqiang; Liu, Liping; Fan, Huimin; Zhou, Yaying; Yao, Yuqin; Zhang, Yue

doi:10.1016/j.bmcl.2017.10.073

Cited by 9 publications

(5 citation statements)

References 23 publications

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“…More importantly, PDK1 is a direct target of miR-379, which functions as a tumor-inhibiting miRNA by targeting PDK1 in OS. Two novel PDK1 inhibitors were shown to concentration-dependently reduce the phosphorylation of the pyruvate dehydrogenase complex in MG-63 OS cells, whose proliferation was inhibited as a result [51].…”

Section: Discussionmentioning

confidence: 99%

Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of osteosarcoma

Zhang

Zheng

Lin

et al. 2020

Aging

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This work aimed to investigate tumor-infiltrating immune cells (TIICs) and immune-associated genes in the tumor microenvironment of osteosarcoma. An algorithm known as ESTIMATE was applied for immune score assessment, and osteosarcoma cases were assigned to the high and low immune score groups. Immuneassociated genes between these groups were compared, and an optimal immune-related risk model was built by Cox regression analyses. The deconvolution algorithm (referred to as CIBERSORT) was applied to assess 22 TIICs for their amounts in the osteosarcoma microenvironment. Osteosarcoma cases with high immune score had significantly improved outcome (P<0.01). The proportions of naive B cells and M0 macrophages were significantly lower in high immune score tissues compared with the low immune score group (P<0.05), while the amounts of M1 macrophages, M2 macrophages, and resting dendritic cells were significantly higher (P<0.05). Important immune-associated genes were determined to generate a prognostic model by Cox regression analysis. Interestingly, cases with high risk score had poor outcome (P<0.01). The areas under the curve (AUC) for the risk model in predicting 1, 3 and 5-year survival were 0.634, 0.781, and 0.809, respectively. Gene set enrichment analysis suggested immunosuppression in high-risk osteosarcoma patients, in association with poor outcome.

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Section: Discussionmentioning

confidence: 99%

Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of osteosarcoma

Zhang

Zheng

Lin

et al. 2020

Aging

133

124

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“…It had been reported that PDK1 was remarkably overexpressed in various tumors such as lung cancer [7], gastric cancer [17],glioblastoma [18], etc. [19][20][21][22][23][24][25], regulated by hypoxia-inducible factor-1α (HIF-1α) mediated [26] or Wnt/β-catenin signaling [27] and contributed to chemoresistance of ovarian cancer by activating EGFR [28]. Michelle K. Y's team had confirmed that PDK1 could promote the development of ovarian cancer especially in metastasis by modulating tumormesothelial adhesion, invasion, and angiogenesis via α5β1 integrin and JNK/IL-8 signaling [29].…”

Section: Ivyspring International Publishermentioning

confidence: 99%

The oncogenic and prognostic role of PDK1 in the progression and metastasis of ovarian cancer

et al. 2021

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“…PDK1 is therefore a good target for cancer therapies, for which inhibitors have been tested. Several compounds able to inhibit PDK1 function resulted in either proliferation inhibition or apoptosis of cancer cells [ 6 , 60 , 61 , 62 ]. Even though we did not detect a significant increase in apoptosis in zebrafish embryos when expressing PDK1 G380D compared to the other groups, we suggest that cells in both the patient and zebrafish embryos may be similarly affected by the lower phosphorylation of PDH.…”

Section: Discussionmentioning

confidence: 99%

“…The key enzyme at the center of PDC activity control is PDH, whose activity is controlled by the balance between the activity of PDH kinases and phosphatases, that in turn sense the metabolic state of the cell [ 2 , 3 ]. PDH is a tetramer composed of 2a and 2b subunits [ 4 ], in which the a subunits are the target for phosphorylation at Ser232, Ser293, and Ser300 [ 5 , 6 ]. Tissue-specific pyruvate dehydrogenase kinases (PDKs) phosphorylate PDH-E1α subunits and render PDC inactive.…”

Section: Introductionmentioning

confidence: 99%

A Missense Variant in PDK1 Associated with Severe Neurodevelopmental Delay and Epilepsy

et al. 2022

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The pyruvate dehydrogenase complex (PDC) is responsible for the conversion of pyruvate into acetyl-CoA, which is used for energy conversion in cells. PDC activity is regulated by phosphorylation via kinases and phosphatases (PDK/PDP). Variants in all subunits of the PDC and in PDK3 have been reported, with varying phenotypes including lactic acidosis, neurodevelopmental delay, peripheral neuropathy, or seizures. Here, we report a de novo heterozygous missense variant in PDK1 (c.1139G > A; p.G380D) in a girl with developmental delay and early onset severe epilepsy. To investigate the role of PDK1G380D in energy metabolism and neuronal development, we used a zebrafish model. In zebrafish embryos we show a reduced number of cells with mitochondria with membrane potential, reduced movements, and a delay in neuronal development. Furthermore, we observe a reduction in the phosphorylation of PDH-E1α by PDKG380D, which suggests a disruption in the regulation of PDC activity. Finally, in patient fibroblasts, a mild reduction in the ratio of phosphorylated PDH over total PDH-E1α was detected. In summary, our findings support the notion that this aberrant PDK1 activity is the cause of clinical symptoms in the patient.

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Identification of pyruvate dehydrogenase kinase 1 inhibitors with anti-osteosarcoma activity

Cited by 9 publications

References 23 publications

Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of osteosarcoma

Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of osteosarcoma

The oncogenic and prognostic role of PDK1 in the progression and metastasis of ovarian cancer

A Missense Variant in PDK1 Associated with Severe Neurodevelopmental Delay and Epilepsy

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