Nuclear Pyruvate Kinase M2 (Pkm2) Contributes To Phosphoserine Aminotransferase 1 (Psat1)-Mediated Cell Migration In Egfr-Activated Lung Cancer Cells
CANCERS(2021)
Abstract
Simple Summary Alternative functions for metabolic proteins have recently been shown to drive cancer growth. These may include differential enzymatic activity or novel protein associations. Phosphoserine aminotransferase 1 (PSAT1) participates in cellular serine synthesis and has been observed to be elevated in different tumor types. In this study, we aimed to identify new putative PSAT1 activities and determine their contribution to lung tumor progression. We found a direct association for PSAT1 with another enzyme, pyruvate kinase M2. While this appears not to affect PKM2's metabolic activity, PSAT1 is required for the specific cellular localization of PKM2 upon tumorigenic signaling. Further, the depletion of PSAT1 suppresses lung cancer cell movement that can be partially restored by the compartment expression of PKM2. These findings reveal a novel mechanism that is able to promote the spread of this deadly disease. An elevated expression of phosphoserine aminotransferase 1 (PSAT1) has been observed in multiple tumor types and is associated with poorer clinical outcomes. Although PSAT1 is postulated to promote tumor growth through its enzymatic function within the serine synthesis pathway (SSP), its role in cancer progression has not been fully characterized. Here, we explore a putative non-canonical function of PSAT1 that contributes to lung tumor progression. Biochemical studies found that PSAT1 selectively interacts with pyruvate kinase M2 (PKM2). Amino acid mutations within a PKM2-unique region significantly reduced this interaction. While PSAT1 loss had no effect on cellular pyruvate kinase activity and PKM2 expression in non-small-cell lung cancer (NSCLC) cells, fractionation studies demonstrated that the silencing of PSAT1 in epidermal growth factor receptor (EGFR)-mutant PC9 or EGF-stimulated A549 cells decreased PKM2 nuclear translocation. Further, PSAT1 suppression abrogated cell migration in these two cell types whereas PSAT1 restoration or overexpression induced cell migration along with an elevated nuclear PKM2 expression. Lastly, the nuclear re-expression of the acetyl-mimetic mutant of PKM2 (K433Q), but not the wild-type, partially restored cell migration in PSAT1-silenced cells. Therefore, we conclude that, in response to EGFR activation, PSAT1 contributes to lung cancer cell migration, in part, by promoting nuclear PKM2 translocation.
MoreTranslated text
Key words
NSCLC, EGFR mutation, motility, phosphoserine aminotransferase 1, pyruvate kinase
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined