FOXM1D potentiates PKM2‐mediated tumor glycolysis and angiogenesis

Abstract

Tumor growth, especially in the late stage, requires adequate nutrients and rich vasculature, in which PKM2 plays a convergent role. It has been reported that PKM2, together with FOXM1D, is upregulated in late-stage colorectal cancer and associated with metastasis; however, their underlying mechanism for promoting tumor progression remains elusive. Herein, we revealed that FOXM1D potentiates PKM2-mediated glycolysis and angiogenesis through multiple protein-protein interactions. In the presence of FBP, FOXM1D binds to tetrameric PKM2 and assembles a heterooctamer, restraining PKM2 metabolic activity by about a half and thereby promoting aerobic glycolysis. Furthermore, FOXM1D interacts with PKM2 and NF-jB and induces their nuclear translocation with the assistance of the nuclear transporter importin 4. Once in the nucleus, PKM2 and NF-jB complexes subsequently augment VEGFA transcription. The increased VEGFA is secreted extracellularly via exosomes, an event potentiated by the interaction of FOXM1 with VPS11, eventually promoting tumor angiogenesis. Based on these findings, our study provides another insight into the role of PKM2 in the regulation of glycolysis and angiogenesis.

FOXM1 regulates glycolysis and energy production in multiple myeloma

“…Thus, silencing PKM2, a pyruvate kinase muscle isozyme that is positively regulated by the Myc-NEK2 axis in myeloma cells [ 42 ], inhibits myeloma [ 43 ]. In sync with that, FOXM1-dependent upregulation of PKM2 promotes glycolysis and the Warburg effect in colon cancer [ 44 ]. HK2, an isoform of hexokinase that is overexpressed in many malignancies including MM [ 45 ], is another promising target in myeloma given that small-drug inhibition of HK2 [ 46 ] or knockdown of HK2 using anti-sense oligonucleotides [ 47 ] kills neoplastic plasma cells with great efficacy.…”

Extracellular vesicles and particles impact the systemic landscape of cancer

“…The angiogenic switch is an essential event to sustain metastatic outgrowth and exit from dormancy and relies on local release of growth factors and recruitment of endothelial progenitor cells from the bone marrow (Gao et al, 2008). In primary tumors, EVPs are prime carriers of pro‐angiogenic factors, such as miRNAs, VEGF‐A, and IL‐6 (Skog et al , 2008; Umezu et al , 2014; Mao et al , 2019b; Zhang et al , 2020d), or induce their synthesis by endothelial cells (Tang et al , 2018a; Sato et al , 2019; He et al , 2019a; Xie et al , 2020a; Song et al , 2021). Moreover, EVPs from primary and potentially secondary melanoma tumors influence the expression of MET oncoproteins in vasculogenic c‐Kit + Tie2 + bone marrow precursors, inducing the activation of a signaling pathway involved in cell motility.…”

Development of an Aerobic Glycolysis Index for Predicting the Sorafenib Sensitivity and Prognosis of Hepatocellular Carcinoma

“…More importantly, the Transwell assay revealed that cell lines with high AGI exhibited the greater invasion capability ( Supplementary Figure 4 ). Previous studies also have reported a close relationship between aerobic glycolysis and angiogenesis ( 42 – 44 ). In the present study, we compared the expression of several genes involved in angiogenesis between the high and low AGI groups.…”