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AMPK maintains TCA cycle through sequential phosphorylation of PDHA to promote tumor metastasis

Cancer represents the leading public health problem throughout the world. Globally, about one out of six deaths is related to cancer, which is largely due to the metastatic lesions. However, there are no effective strategies for targeting cancer metastasis. Identification of the key druggable target...

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Autores principales: Cai, Zhen, Peng, Danni, Lin, Hui-Kuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Shared Science Publishers OG 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713264/
https://www.ncbi.nlm.nih.gov/pubmed/33336150
http://dx.doi.org/10.15698/cst2020.12.238
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author Cai, Zhen
Peng, Danni
Lin, Hui-Kuan
author_facet Cai, Zhen
Peng, Danni
Lin, Hui-Kuan
author_sort Cai, Zhen
collection PubMed
description Cancer represents the leading public health problem throughout the world. Globally, about one out of six deaths is related to cancer, which is largely due to the metastatic lesions. However, there are no effective strategies for targeting cancer metastasis. Identification of the key druggable targets maintaining metastasis is crucial for cancer treatment. In our recent study (Cai et al. (2020), Mol Cell, doi: 10.1016/j.molcel.2020.09.018), we found that activity of AMPK was enriched in metastatic tumors compared to primary tumors. Depletion of AMPK rendered cancer cells more sensitive to metabolic and oxidative stress, leading to the impairment of breast cancer lung metastasis. Activation of AMPK rewired cancer metabolism towards TCA cycle, which protects disseminated cancer cells from both metabolic and oxidative stress-induced cell death, and facilitates cancer metastasis. Further, AMPK critically maintained the activity of pyruvate dehydrogenase complex (PDH), the rate limiting enzyme involved in TCA cycle, thus favoring the pyruvate metabolism towards TCA cycle rather than converting it to lactate. Mechanistically, AMPK was shown to co-localize with PDHA, the catalytic subunit of PDH, in the mitochondrial matrix and directly triggered the phosphorylation of PDHA on Ser295 and Ser314. Hyper-phosphorylation of Ser295 and Ser314 of PDHA promotes lung metastasis through elevating activity of PDH. Of note, PDHA Ser314 phosphorylation abrogated the interaction between PDHA and PDHKs leading to the dephosphorylation on previously reported S293 site, whose phosphorylation serves as a negative signal for PDH activation, while S295 phosphorylation serves as an intrinsic catalytic site required for pyruvate metabolism. Our study presented the first evidence for the pro-metastatic property of the AMPK-PDH axis and advance our current understanding of how PDH is activated under physiological and pathological conditions.
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spelling pubmed-77132642020-12-16 AMPK maintains TCA cycle through sequential phosphorylation of PDHA to promote tumor metastasis Cai, Zhen Peng, Danni Lin, Hui-Kuan Cell Stress Microreview Cancer represents the leading public health problem throughout the world. Globally, about one out of six deaths is related to cancer, which is largely due to the metastatic lesions. However, there are no effective strategies for targeting cancer metastasis. Identification of the key druggable targets maintaining metastasis is crucial for cancer treatment. In our recent study (Cai et al. (2020), Mol Cell, doi: 10.1016/j.molcel.2020.09.018), we found that activity of AMPK was enriched in metastatic tumors compared to primary tumors. Depletion of AMPK rendered cancer cells more sensitive to metabolic and oxidative stress, leading to the impairment of breast cancer lung metastasis. Activation of AMPK rewired cancer metabolism towards TCA cycle, which protects disseminated cancer cells from both metabolic and oxidative stress-induced cell death, and facilitates cancer metastasis. Further, AMPK critically maintained the activity of pyruvate dehydrogenase complex (PDH), the rate limiting enzyme involved in TCA cycle, thus favoring the pyruvate metabolism towards TCA cycle rather than converting it to lactate. Mechanistically, AMPK was shown to co-localize with PDHA, the catalytic subunit of PDH, in the mitochondrial matrix and directly triggered the phosphorylation of PDHA on Ser295 and Ser314. Hyper-phosphorylation of Ser295 and Ser314 of PDHA promotes lung metastasis through elevating activity of PDH. Of note, PDHA Ser314 phosphorylation abrogated the interaction between PDHA and PDHKs leading to the dephosphorylation on previously reported S293 site, whose phosphorylation serves as a negative signal for PDH activation, while S295 phosphorylation serves as an intrinsic catalytic site required for pyruvate metabolism. Our study presented the first evidence for the pro-metastatic property of the AMPK-PDH axis and advance our current understanding of how PDH is activated under physiological and pathological conditions. Shared Science Publishers OG 2020-11-25 /pmc/articles/PMC7713264/ /pubmed/33336150 http://dx.doi.org/10.15698/cst2020.12.238 Text en Copyright: © 2020 Cai et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
spellingShingle Microreview
Cai, Zhen
Peng, Danni
Lin, Hui-Kuan
AMPK maintains TCA cycle through sequential phosphorylation of PDHA to promote tumor metastasis
title AMPK maintains TCA cycle through sequential phosphorylation of PDHA to promote tumor metastasis
title_full AMPK maintains TCA cycle through sequential phosphorylation of PDHA to promote tumor metastasis
title_fullStr AMPK maintains TCA cycle through sequential phosphorylation of PDHA to promote tumor metastasis
title_full_unstemmed AMPK maintains TCA cycle through sequential phosphorylation of PDHA to promote tumor metastasis
title_short AMPK maintains TCA cycle through sequential phosphorylation of PDHA to promote tumor metastasis
title_sort ampk maintains tca cycle through sequential phosphorylation of pdha to promote tumor metastasis
topic Microreview
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713264/
https://www.ncbi.nlm.nih.gov/pubmed/33336150
http://dx.doi.org/10.15698/cst2020.12.238
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