PMID- 32825675
OWN - NLM
STAT- MEDLINE
DCOM- 20210414
LR  - 20210414
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 21
IP  - 17
DP  - 2020 Aug 21
TI  - Ilimaquinone Induces the Apoptotic Cell Death of Cancer Cells by Reducing 
      Pyruvate Dehydrogenase Kinase 1 Activity.
LID - 10.3390/ijms21176021 [doi]
LID - 6021
AB  - 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 E1alpha 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.
FAU - Kwak, Choong-Hwan
AU  - Kwak CH
AD  - Korean Medical Research Center for Healthy Aging School of Korean Medicine, Pusan 
      National University, Yangsan, Gyeongnam 50612, Korea.
FAU - Jin, Ling
AU  - Jin L
AD  - Department of Korean Medical Science, School of Korean Medicine, Pusan National 
      University, Yangsan, Gyeongnam 50612, Korea.
FAU - Han, Jung Ho
AU  - Han JH
AD  - Department of Korean Medical Science, School of Korean Medicine, Pusan National 
      University, Yangsan, Gyeongnam 50612, Korea.
FAU - Han, Chang Woo
AU  - Han CW
AD  - Department of Molecular Biology, College of Natural Sciences, Pusan National 
      University, Geumjung-gu, Busan 46241, Korea.
FAU - Kim, Eonmi
AU  - Kim E
AD  - National Institute for Korean Medicine Development, Gyeongsan, Gyeongbuk 38540, 
      Korea.
FAU - Cho, MyoungLae
AU  - Cho M
AD  - National Institute for Korean Medicine Development, Gyeongsan, Gyeongbuk 38540, 
      Korea.
FAU - Chung, Tae-Wook
AU  - Chung TW
AD  - Korean Medical Research Center for Healthy Aging School of Korean Medicine, Pusan 
      National University, Yangsan, Gyeongnam 50612, Korea.
FAU - Bae, Sung-Jin
AU  - Bae SJ
AUID- ORCID: 0000-0001-8975-0876
AD  - Korean Medical Research Center for Healthy Aging School of Korean Medicine, Pusan 
      National University, Yangsan, Gyeongnam 50612, Korea.
FAU - Jang, Se Bok
AU  - Jang SB
AD  - Department of Molecular Biology, College of Natural Sciences, Pusan National 
      University, Geumjung-gu, Busan 46241, Korea.
FAU - Ha, Ki-Tae
AU  - Ha KT
AUID- ORCID: 0000-0001-6283-0171
AD  - Korean Medical Research Center for Healthy Aging School of Korean Medicine, Pusan 
      National University, Yangsan, Gyeongnam 50612, Korea.
AD  - Department of Korean Medical Science, School of Korean Medicine, Pusan National 
      University, Yangsan, Gyeongnam 50612, Korea.
LA  - eng
GR  - 2014R1A5A20009936/National Research Foundation of Korea/
GR  - 2019R1I1A1A01062912/National Research Foundation of Korea/
PT  - Journal Article
DEP - 20200821
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Antineoplastic Agents)
RN  - 0 (PDK1 protein, human)
RN  - 0 (Pyruvate Dehydrogenase Acetyl-Transferring Kinase)
RN  - 0 (Quinones)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Sesquiterpenes)
RN  - 5U0WAN3N8Q (ilimaquinone)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 1.2.4.1 (Pyruvate Dehydrogenase (Lipoamide))
RN  - EC 1.2.4.1 (pyruvate dehydrogenase E1alpha subunit)
SB  - IM
MH  - A549 Cells
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/*drug effects/physiology
MH  - Carcinoma, Lewis Lung
MH  - Cell Line, Tumor
MH  - Humans
MH  - Mice
MH  - Mitochondria/drug effects/metabolism
MH  - Phosphorylation/drug effects
MH  - Porifera/chemistry
MH  - Pyruvate Dehydrogenase (Lipoamide)/genetics/metabolism
MH  - Pyruvate Dehydrogenase Acetyl-Transferring Kinase/antagonists & 
      inhibitors/chemistry/*metabolism
MH  - Quinones/*pharmacology
MH  - Reactive Oxygen Species/metabolism
MH  - Sesquiterpenes/*pharmacology
PMC - PMC7504051
OTO - NOTNLM
OT  - Warburg effect
OT  - apoptosis
OT  - glycolysis
OT  - ilimaquinone
OT  - pyruvate dehydrogenase kinase 1
COIS- The authors declare no conflict of interest.
EDAT- 2020/08/23 06:00
MHDA- 2021/04/15 06:00
PMCR- 2020/09/01
CRDT- 2020/08/23 06:00
PHST- 2020/06/25 00:00 [received]
PHST- 2020/08/07 00:00 [revised]
PHST- 2020/08/20 00:00 [accepted]
PHST- 2020/08/23 06:00 [entrez]
PHST- 2020/08/23 06:00 [pubmed]
PHST- 2021/04/15 06:00 [medline]
PHST- 2020/09/01 00:00 [pmc-release]
AID - ijms21176021 [pii]
AID - ijms-21-06021 [pii]
AID - 10.3390/ijms21176021 [doi]
PST - epublish
SO  - Int J Mol Sci. 2020 Aug 21;21(17):6021. doi: 10.3390/ijms21176021.