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bioRxiv · 10.1101/2022.01.11.475954

Vitamin C functions as double-edge sword on cancer progression depending on ERK activation or inhibition mediated by its receptor SVCT2

Guan, Y.·Chen, B.·Wu, Y.·Han, Z.·Xu, H.·Zhang, C.·Hao, W.·Gao, W.·Guo, Z.
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Abstract

The effect of Vitamin C (Vc) in oncotherapy was controversial for decades. And hyperactivation of extracellular signal-regulated kinase (ERK) drove tumorigenesis. Herein, we demonstrated that Vc activated ERK through sodium-dependent Vc transporter 2 (SVCT2), while high-dose Vc resulted in persistent ERK feedback inhibition following activation. Extracellular Vc binding to SVCT2 initiated ERK activation, then transmembrane transport of Vc induced dimerization of SVCT2. Activated ERK phosphorylated protein tyrosine phosphatase non-receptor type 12 (PTPN12) at Ser434 and inhibited PTPN12 activity, thus enhancing phosphorylation of Janus kinase 2 (JAK2), which phosphorylated growth factor receptor bound protein 2 (GRB2) at Tyr160 to promote GRB2 dimers dissociation and recruitment of GRB2 to SVCT2, leading to further ERK activation. Different cancers have different sensitivities to Vc, the dose effects of Vc on cancer phenotypes depended on that ERK was activated or inhibited. These findings suggest SVCT2 is a Vc receptor mediating the ERK-PTPN12-JAK2-GRB2-ERK positive feedback loop and a potential target for oncotherapy. Abstract graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/475954v2_ufig1.gif" ALT="Figure 1"> View larger version (72K): org.highwire.dtl.DTLVardef@9f75e7org.highwire.dtl.DTLVardef@f5bc18org.highwire.dtl.DTLVardef@10fe4c4org.highwire.dtl.DTLVardef@742b7d_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Guan, Y., Chen, B., Wu, Y., Han, Z., Xu, H., Zhang, C., Hao, W., Gao, W., Guo, Z.. 2022-01-12. Vitamin C functions as double-edge sword on cancer progression depending on ERK activation or inhibition mediated by its receptor SVCT2. https://doi.org/10.1101/2022.01.11.475954

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