Cargando…
Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity
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 E1...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504051/ https://www.ncbi.nlm.nih.gov/pubmed/32825675 http://dx.doi.org/10.3390/ijms21176021 |
_version_ | 1783584534900506624 |
---|---|
author | Kwak, Choong-Hwan Jin, Ling Han, Jung Ho Han, Chang Woo Kim, Eonmi Cho, MyoungLae Chung, Tae-Wook Bae, Sung-Jin Jang, Se Bok Ha, Ki-Tae |
author_facet | Kwak, Choong-Hwan Jin, Ling Han, Jung Ho Han, Chang Woo Kim, Eonmi Cho, MyoungLae Chung, Tae-Wook Bae, Sung-Jin Jang, Se Bok Ha, Ki-Tae |
author_sort | Kwak, Choong-Hwan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7504051 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75040512020-09-24 Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity Kwak, Choong-Hwan Jin, Ling Han, Jung Ho Han, Chang Woo Kim, Eonmi Cho, MyoungLae Chung, Tae-Wook Bae, Sung-Jin Jang, Se Bok Ha, Ki-Tae Int J Mol Sci Article 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. MDPI 2020-08-21 /pmc/articles/PMC7504051/ /pubmed/32825675 http://dx.doi.org/10.3390/ijms21176021 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kwak, Choong-Hwan Jin, Ling Han, Jung Ho Han, Chang Woo Kim, Eonmi Cho, MyoungLae Chung, Tae-Wook Bae, Sung-Jin Jang, Se Bok Ha, Ki-Tae Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity |
title | Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity |
title_full | Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity |
title_fullStr | Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity |
title_full_unstemmed | Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity |
title_short | Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing Pyruvate Dehydrogenase Kinase 1 Activity |
title_sort | ilimaquinone induces the apoptotic cell death of cancer cells by reducing pyruvate dehydrogenase kinase 1 activity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504051/ https://www.ncbi.nlm.nih.gov/pubmed/32825675 http://dx.doi.org/10.3390/ijms21176021 |
work_keys_str_mv | AT kwakchoonghwan ilimaquinoneinducestheapoptoticcelldeathofcancercellsbyreducingpyruvatedehydrogenasekinase1activity AT jinling ilimaquinoneinducestheapoptoticcelldeathofcancercellsbyreducingpyruvatedehydrogenasekinase1activity AT hanjungho ilimaquinoneinducestheapoptoticcelldeathofcancercellsbyreducingpyruvatedehydrogenasekinase1activity AT hanchangwoo ilimaquinoneinducestheapoptoticcelldeathofcancercellsbyreducingpyruvatedehydrogenasekinase1activity AT kimeonmi ilimaquinoneinducestheapoptoticcelldeathofcancercellsbyreducingpyruvatedehydrogenasekinase1activity AT chomyounglae ilimaquinoneinducestheapoptoticcelldeathofcancercellsbyreducingpyruvatedehydrogenasekinase1activity AT chungtaewook ilimaquinoneinducestheapoptoticcelldeathofcancercellsbyreducingpyruvatedehydrogenasekinase1activity AT baesungjin ilimaquinoneinducestheapoptoticcelldeathofcancercellsbyreducingpyruvatedehydrogenasekinase1activity AT jangsebok ilimaquinoneinducestheapoptoticcelldeathofcancercellsbyreducingpyruvatedehydrogenasekinase1activity AT hakitae ilimaquinoneinducestheapoptoticcelldeathofcancercellsbyreducingpyruvatedehydrogenasekinase1activity |