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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| Format: | Article |
| Language: | English |
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Shared Science Publishers OG
2020-11-01
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| Series: | Cell Stress |
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| Online Access: | http://www.cell-stress.com/researcharticles/2020a-cai-cell-stress/ |
| _version_ | 1829493166136360960 |
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| author | Zhen Cai Danni Peng Hui-Kuan Lin |
| author_facet | Zhen Cai Danni Peng Hui-Kuan Lin |
| author_sort | Zhen Cai |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-16T06:29:39Z |
| format | Article |
| id | doaj.art-52fb924084a04736816841a66cf23cb3 |
| institution | Directory Open Access Journal |
| issn | 2523-0204 |
| language | English |
| last_indexed | 2024-12-16T06:29:39Z |
| publishDate | 2020-11-01 |
| publisher | Shared Science Publishers OG |
| record_format | Article |
| series | Cell Stress |
| spelling | doaj.art-52fb924084a04736816841a66cf23cb32022-12-21T22:40:56ZengShared Science Publishers OGCell Stress2523-02042020-11-0141227327710.15698/cst2020.12.238AMPK maintains TCA cycle through sequential phosphorylation of PDHA to promote tumor metastasisZhen Cai0Danni Peng1Hui-Kuan Lin2Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.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.http://www.cell-stress.com/researcharticles/2020a-cai-cell-stress/cancer metastasismetabolic stressoxidative stressampkpdhatca cycle |
| spellingShingle | Zhen Cai Danni Peng Hui-Kuan Lin AMPK maintains TCA cycle through sequential phosphorylation of PDHA to promote tumor metastasis Cell Stress cancer metastasis metabolic stress oxidative stress ampk pdha tca cycle |
| 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 | cancer metastasis metabolic stress oxidative stress ampk pdha tca cycle |
| url | http://www.cell-stress.com/researcharticles/2020a-cai-cell-stress/ |
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