GLUT3 Promotes Epithelial–Mesenchymal Transition via TGF-β/JNK/ATF2 Signaling Pathway in Colorectal Cancer Cells

Abstract

Glucose transporter (GLUT) 3, a member of the GLUTs family, is involved in cellular glucose utilization and the first step in glycolysis. GLUT3 is highly expressed in colorectal cancer (CRC) and it leads to poor prognosis to CRC patient outcome. However, the molecular mechanisms of GLUT3 on the epithelial–mesenchymal transition (EMT) process in metastatic CRC is not yet clear. Here, we identified that activation of the c-Jun N-terminal kinase (JNK)/activating transcription factor-2 (ATF2) signaling pathway by transforming growth factor-β (TGF-β) promotes GLUT3-induced EMT in CRC cells. The regulation of GLUT3 expression was significantly associated with EMT-related markers such as E-cadherin, α- smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), vimentin and zinc finger E-box binding homeobox 1 (ZEB1). We also found that GLUT3 accelerated the invasive ability of CRC cells. Mechanistically, TGF-β induced the expression of GLUT3 through the phosphorylation of JNK/ATF2, one of the SMAD-independent pathways. TGF-β induced the expression of GLUT3 by increasing the phosphorylation of JNK, the nuclear translocation of the ATF2 transcription factor, and the binding of ATF2 to the promoter region of GLUT3, which increased EMT in CRC cells. Collectively, our results provide a new comprehensive mechanism that GLUT3 promotes EMT process through the TGF-β/JNK/ATF2 signaling pathway, which could be a potential target for the treatment of metastatic CRC.

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“…The classic form of metabolic reprogramming in cancer cells is the alteration in glucose metabolism. Elevated expression of glucose transporters, such as Glut1/Glut3 on cell membranes, causes increased glucose consumption in cancer cells [ 39 , 40 ]. Metabolic intermediates synthesized by glucose metabolism enhance the biosynthesis of nucleotides, amino acids, and triglycerides.…”

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“…The stomach tissues were homogenized with ice-cold cell lysis buffer (Cell Signaling, Danvers, MA, USA) plus phosphatase and protease inhibitors (Roche Applied Science, Mannheim, Germany), and then centrifuged. Western blot analysis was performed as previously described [ 33 ]. Proteins were visualized using an enhanced chemiluminescence system (Thermo Fisher Scientific, Waltham, MA, USA).…”

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“…Further research found that GLUT1 gene regulates TGF-β/PI3K AKT mTOR signal affects many biological behaviors of CRC cells [15]. Moreover, GLUT3, a homologous family member of GLUT1, was highly expressed in CRC and negatively linked to CRC patient prognosis [16].…”