AMPK maintains TCA cycle through sequential phosphorylation of PDHA to promote tumor metastasis
Authors:Zhen Cai1,#, Danni Peng1,# and Hui-Kuan Lin1
1 Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
# These authors contributed equally to this article.
Keywords:
cancer metastasis, metabolic stress, oxidative stress, AMPK, PDHA, TCA cycle.
Corresponding Author(s):
Conflict of interest statement:
The authors declare no competing interests.
Please cite this article as:
Zhen Cai, Danni Peng and Hui-Kuan Lin (2020). AMPK maintains TCA cycle through sequential phosphorylation of PDHA to promote tumor metastasis. Cell Stress 4(12): 273-277. doi: 10.15698/cst2020.12.238
© 2020 Cai et al. 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 reproduc-tion in any medium, provided the original author and source are acknowledged.
Abstract:
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.