Pyruvate dehydrogenase kinase 1 contributes to cisplatin resistance of ovarian cancer through EGFR activation

Zhang, Meng; Cong, Qing; Zhang, Xiaoyan; Zhang, Mingxing; Lu, Yingying; Xu, Congjian

doi:10.1002/jcp.27369

Cited by 42 publications

(36 citation statements)

References 29 publications

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“…In the PDHA1-knockout cells, cell viability was partially rescued by about 40% compared with IQ-treated wild type A549 cells. The results might due to off-targets of IQ or another target of PDK1, including EGFR, HGF-MET, and PARL [22][23][24]. Thus, we suggest that IQ significantly induced mitochondrial ROS production by inhibiting PDK1 activity and thereby induced apoptotic cell death in the A549 lung cancer cells.…”

Section: Discussionmentioning

confidence: 74%

Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity

Kwak

Han

et al. 2020

IJMS

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In cancer cells, aerobic glycolysis rather than oxidative phosphorylation (OxPhos) is generally preferred for the production of ATP. In many cancers, highly expressed pyruvate dehydrogenase kinase 1 (PDK1) reduces the activity of pyruvate dehydrogenase (PDH) by inducing the phosphorylation of its E1α subunit (PDHA1) and subsequently, shifts the energy metabolism from OxPhos to aerobic glycolysis. Thus, PDK1 has been regarded as a target for anticancer treatment. Here, we report that ilimaquinone (IQ), a sesquiterpene quinone isolated from the marine sponge Smenospongia cerebriformis, might be a novel PDK1 inhibitor. IQ decreased the cell viability of human and murine cancer cells, such as A549, DLD-1, RKO, and LLC cells. The phosphorylation of PDHA1, the substrate of PDK1, was reduced by IQ in the A549 cells. IQ decreased the levels of secretory lactate and increased oxygen consumption. The anticancer effect of IQ was markedly reduced in PDHA1-knockout cells. Computational simulation and biochemical assay revealed that IQ interfered with the ATP binding pocket of PDK1 without affecting the interaction of PDK1 and the E2 subunit of the PDH complex. In addition, similar to other pyruvate dehydrogenase kinase inhibitors, IQ induced the generation of mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in the A549 cells. The apoptotic cell death induced by IQ treatment was rescued in the presence of MitoTEMPO, a mitochondrial ROS inhibitor. In conclusion, we suggest that IQ might be a novel candidate for anticancer therapeutics that act via the inhibition of PDK1 activity.

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Section: Discussionmentioning

confidence: 74%

Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity

Kwak

Han

et al. 2020

IJMS

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“…PDK1, a key enzyme regulates glucose metabolism, attenuates ROS production and prevents hypoxia-induced apoptosis 34 . Zhang et al 35 has reported that PDK1 stimulates EMT program, resistance to cisplatin and increases ovarian cancer growth. In addition, it has been recognized as a gatekeeper of the Warburg effect 35 through inhibition of PDH enzyme, , c, d, e, f) show the UCP2, PDK1, PDH, AMPK and MCT1 expression in T24 cell line after E. coli infection at different MOI and durations, compared to uninfected T24 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Zhang et al 35 has reported that PDK1 stimulates EMT program, resistance to cisplatin and increases ovarian cancer growth. In addition, it has been recognized as a gatekeeper of the Warburg effect 35 through inhibition of PDH enzyme, , c, d, e, f) show the UCP2, PDK1, PDH, AMPK and MCT1 expression in T24 cell line after E. coli infection at different MOI and durations, compared to uninfected T24 cells. #, ## express the significant difference (p ≤ 0.01) and (p ≤ 0.001) of gene expression with respect to the infection duration and MOI respectively, obtained by one-way ANOVA.…”

Section: Discussionmentioning

confidence: 99%

Escherichia coli foster bladder cancer cell line progression via epithelial mesenchymal transition, stemness and metabolic reprogramming

Abd-El-Raouf

Ouf

Gabr

et al. 2020

Sci Rep

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Bacteria is recognized as opportunistic tumor inhabitant, giving rise to an environmental stress that may alter tumor microenvironment, which directs cancer behavior. In vitro infection of the T24 cell line with E. coli was performed to study the bacterial impact on bladder cancer cells. EMT markers were assessed using immunohistochemistry, western blot and RT-PCR. Stemness characteristics were monitored using RT-PCR. Furthermore, the metabolic reprograming was investigated by detection of ROS and metabolic markers. A significant (p ≤ 0.001) upregulation of vimentin as well as downregulation of CK19 transcription and protein levels was reported. A significant increase (p ≤ 0.001) in the expression level of stemness markers (CD44, NANOG, SOX2 and OCT4) was reported. ROS level was elevated, that led to a significant increase (p ≤ 0.001) in UCP2. This enhanced a significant increase (p ≤ 0.001) in PDK1 to significantly downregulate PDH (p ≤ 0.001) in order to block oxidative phosphorylation in favor of glycolysis. This resulted in a significant decrease (p ≤ 0.001) of AMPK, and a significant elevation (p ≤ 0.001) of MCT1 to export the produced lactate to extracellular matrix. Thus, bacteria may induce alteration to the heterogonous tumor cell population through EMT, CSCs and metabolic reprogramming, which may improve cancer cell ability to migrate and self-renew.

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“…Dicumarol, a coumarin compound, has been found to inhibit PDK1 and suppress ovarian cancer tumor growth in vivo 22 . A recent study demonstrated PDK1 contributes to cisplatin resistance of ovarian cancer through EGFR activation and promotes epithelial-mesenchymal transition 23 . In this study, we focused on the clinical significance, functional roles, and downstream mechanisms of PDK1 in ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

PDK1 promotes ovarian cancer metastasis by modulating tumor-mesothelial adhesion, invasion, and angiogenesis via α5β1 integrin and JNK/IL-8 signaling

et al. 2020

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Ovarian cancer is the most lethal gynecological malignancies owing to the lack of definitive symptoms until development of widespread metastases. Identification of novel prognostic and therapeutic targets is therefore an urgent need to improve survival. Here, we demonstrated high expression of the mitochondrial gatekeeping enzyme, pyruvate dehydrogenase kinase 1 (PDK1), in both clinical samples and cell lines of ovarian cancer. PDK1 expression was significantly associated with metastasis, reduced chemosensitivity, and poor overall and disease-free survival, and further highlighted as an independent prognostic factor. Silencing of PDK1 retarded lactate production, ovarian cancer cell adhesion, migration, invasion, and angiogenesis, and consequently metastasis, concomitant with decreased α5β1 integrin expression. Phospho-kinase array profiling and RNA sequencing analyses further revealed reduction of JNK activation and IL-8 expression in PDK1-depleted cells. Conversely, PDK1 overexpression promoted cell adhesion via modulation of α5β1 integrins, along with cell migration, invasion, and angiogenesis through activation of JNK/IL-8 signaling. PDK1 depletion additionally hindered tumor growth and dissemination in nude mice in vivo. Importantly, PDK1 levels were upregulated upon treatment with conditioned medium from omental tissues, which in turn promoted metastasis. Our findings suggest that PDK1, which is regulated by the tumor microenvironment, controls lactate production and promotes ovarian cancer cell metastasis via modulation of α5β1 integrin and JNK/IL-8 signaling. To our knowledge, this is the first report to demonstrate an association between PDK1 and survival in patients with ovarian cancer, supporting its efficacy as a valuable prognostic marker and therapeutic molecular target for the disease. Oncogenesis 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,;Oncogenesis

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Pyruvate dehydrogenase kinase 1 contributes to cisplatin resistance of ovarian cancer through EGFR activation

Cited by 42 publications

References 29 publications

Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity

Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity

Escherichia coli foster bladder cancer cell line progression via epithelial mesenchymal transition, stemness and metabolic reprogramming

PDK1 promotes ovarian cancer metastasis by modulating tumor-mesothelial adhesion, invasion, and angiogenesis via α5β1 integrin and JNK/IL-8 signaling

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