PDGF‐BB/PDGFRβ promotes epithelial–mesenchymal transition by affecting PI3K/AKT/mTOR‐driven aerobic glycolysis in Wilms' tumor G401 cells

Abstract

Wilms' tumor (WT) is the most common pediatric renal malignancy. PDGFRβ belongs to the type III receptor tyrosine kinase family and is known to be involved in tumor metastasis and angiogenesis. Here, we studied the effect and underlying mechanism of PDGFRβ on WT G401 cells. Transwell assay and wound-healing assay were used to detect the effect of PDGFRβ on G401 cells invasion and migration. Western blot and immunofluorescence were used to detect the expression of EMT-related genes. The expression of PI3K/AKT/mTOR pathway proteins was detected by Western blot.The relationship between PDGFRβ and aerobic glycolysis was studied by assessing the expression of glycolysis-related enzymes detected by qRT-PCR and Western blot.The activity of HK, PK, and LDH was detected by corresponding enzyme activity kits.The concentration of lactic acid and glucose was detected by Lactic Acid Assay Kit and Glucose Assay Kit-glucose oxidase method separately. To investigate the mechanism of PDGFRβ in the development of WT, the changes of glucose and lactic acid were analyzed after blocking PI3K pathway, aerobic glycolysis, or PDGFRβ. The key enzyme was screened by Western blot and glucose metabolism experiment after HK2, PKM2, and PDK1 were inhibited. The results showed that PDGFRβ promoted the EMT process by modulating aerobic glycolysis through PI3K/AKT/mTOR pathway in which PKM2 plays a key role. Therefore, our study of the mechanism of PDGFRβ in G401 cells provides a new target for the treatment of WT.

Targeting UBR5 inhibits postsurgical breast cancer lung metastases by inducing CDC73 and p53 mediated apoptosis

“…20 PDGFRβ has been demonstrated to promotes the invasion and migration of mammary tumors by regulating EMT via the PI3K/AKT/mTOR pathway. [21][22][23] Conversely, Lama3, Areg invasion-related markers (MMP2 and MMP9) and EMT-related proteins (N-cadherin and vimentin) in lung adenocarcinoma cells. 24 Amphiregulin (AREG) is one of several ligands capable of binding and activating the epidermal growth factor receptor (EGFR) 25,26 and accelerating the MET process during reprogramming.…”

“…In this context, it is noteworthy that, compared to the WT control, UBR5‐deficient tumor cells exhibited increased expression of PDGFRβ, whose signaling in carcinomas is well established with respect to angiogenesis 20 . PDGFRβ has been demonstrated to promotes the invasion and migration of mammary tumors by regulating EMT via the PI3K/AKT/mTOR pathway 21‐23 . Conversely, Lama3 , Areg and Itga2 were downregulated in UBR5‐deficient cells.…”

Targeting UBR5 inhibits postsurgical breast cancer lung metastases by inducing apoptosis mediated by CDC73 and p53

“…Compared to the WT control, UBR5-de cient tumor cells exhibit increased expression of PDGFRβ, whose signaling in carcinomas is well established with respect to angiogenesis (32). Studies have also shown that PDGFRβ promotes invasion and migration of mammary tumors and malignant renal carcinoma by regulating EMT via the PI3K/AKT/mTOR pathway (26,33,34). PDGF-BB/PDGFRs induce cell migration out of epithelial cell clusters (ECCs) to form a monolayer of broblast-like cells resembling the original de-differentiated cells (DIDs) in morphology, and a PDGFR inhibitor blocks PDGF-BB-induced EMT and stimulates ECCs (35).…”

Targeting UBR5 inhibits postsurgical breast cancer lung metastases mediated by CDC73 and p53

“…Compared to the WT control, UBR5-de cient tumor cells exhibit increased expression of PDGFRβ, whose signaling in carcinomas is well established with respect to angiogenesis (30). Studies have also shown that PDGFRβ promotes invasion and migration of mammary tumors and malignant renal carcinoma by regulating EMT via the PI3K/AKT/mTOR pathway (24,31,32). PDGF-BB/PDGFRs induce cell migration out of epithelial cell clusters (ECCs) to form a monolayer of broblast-like cells resembling the original de-differentiated cells (DIDs) in morphology, and a PDGFR inhibitor blocks PDGF-BB-induced EMT and stimulates ECCs (33).…”