Src Mediates Epigallocatechin-3-<i>O</i>-Gallate-Elicited Acid Sphingomyelinase Activation
Epigallocatechin-3-<i>O</i>-gallate (EGCG) is one of the major bioactive compounds known to be present in green tea. We previously reported that EGCG shows selective toxicity through activation of the protein kinase B (Akt)/cyclic guanosine monophosphate (cGMP)/acid sphingomyelinase (ASM...
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MDPI AG
2020-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/22/5481 |
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| author | Motofumi Kumazoe Mai Kadomatsu Jaehoon Bae Yushi Otsuka Yoshinori Fujimura Hirofumi Tachibana |
| author_facet | Motofumi Kumazoe Mai Kadomatsu Jaehoon Bae Yushi Otsuka Yoshinori Fujimura Hirofumi Tachibana |
| author_sort | Motofumi Kumazoe |
| collection | DOAJ |
| description | Epigallocatechin-3-<i>O</i>-gallate (EGCG) is one of the major bioactive compounds known to be present in green tea. We previously reported that EGCG shows selective toxicity through activation of the protein kinase B (Akt)/cyclic guanosine monophosphate (cGMP)/acid sphingomyelinase (ASM) axis via targeting its receptor 67-kDa laminin receptor (67LR), which is overexpressed in cancer. However, little is known about upstream mechanisms of EGCG-elicited ASM activation. In this study we show that the proto-oncogene tyrosine-protein kinase Src, also known as c-src, plays a crucial role in the anticancer effect of EGCG. We showed that EGCG elicits phosphorylation of Src at Tyr 416, a crucial phosphorylation site for its activity, and that the pharmacological inhibition of Src impedes the upstream events in EGCG-induced cell death signaling including upregulation of Akt activity, increase in cGMP levels, and activation of ASM. Moreover, focal adhesion kinase (FAK), which is involved in the phosphorylation of Src, is colocalized with 67LR. EGCG treatment enhanced interaction of FAK and 67LR. Consistent with these findings, pharmacological inhibition of FAK significantly neutralized EGCG-induced upregulation of Akt activity and activation of ASM. Taken together, FAK/Src play crucial roles in the upstream signaling of EGCG. |
| first_indexed | 2024-03-10T14:37:32Z |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T14:37:32Z |
| publishDate | 2020-11-01 |
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| series | Molecules |
| spelling | doaj.art-0dd44c2ed5554c2a9f6673af7dad297d2023-11-20T21:59:58ZengMDPI AGMolecules1420-30492020-11-012522548110.3390/molecules25225481Src Mediates Epigallocatechin-3-<i>O</i>-Gallate-Elicited Acid Sphingomyelinase ActivationMotofumi Kumazoe0Mai Kadomatsu1Jaehoon Bae2Yushi Otsuka3Yoshinori Fujimura4Hirofumi Tachibana5Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, JapanDivision of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, JapanDivision of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, JapanDivision of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, JapanDivision of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, JapanDivision of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, JapanEpigallocatechin-3-<i>O</i>-gallate (EGCG) is one of the major bioactive compounds known to be present in green tea. We previously reported that EGCG shows selective toxicity through activation of the protein kinase B (Akt)/cyclic guanosine monophosphate (cGMP)/acid sphingomyelinase (ASM) axis via targeting its receptor 67-kDa laminin receptor (67LR), which is overexpressed in cancer. However, little is known about upstream mechanisms of EGCG-elicited ASM activation. In this study we show that the proto-oncogene tyrosine-protein kinase Src, also known as c-src, plays a crucial role in the anticancer effect of EGCG. We showed that EGCG elicits phosphorylation of Src at Tyr 416, a crucial phosphorylation site for its activity, and that the pharmacological inhibition of Src impedes the upstream events in EGCG-induced cell death signaling including upregulation of Akt activity, increase in cGMP levels, and activation of ASM. Moreover, focal adhesion kinase (FAK), which is involved in the phosphorylation of Src, is colocalized with 67LR. EGCG treatment enhanced interaction of FAK and 67LR. Consistent with these findings, pharmacological inhibition of FAK significantly neutralized EGCG-induced upregulation of Akt activity and activation of ASM. Taken together, FAK/Src play crucial roles in the upstream signaling of EGCG.https://www.mdpi.com/1420-3049/25/22/5481SrcEGCGanticancer effectFAKsensing molecule67LR |
| spellingShingle | Motofumi Kumazoe Mai Kadomatsu Jaehoon Bae Yushi Otsuka Yoshinori Fujimura Hirofumi Tachibana Src Mediates Epigallocatechin-3-<i>O</i>-Gallate-Elicited Acid Sphingomyelinase Activation Molecules Src EGCG anticancer effect FAK sensing molecule 67LR |
| title | Src Mediates Epigallocatechin-3-<i>O</i>-Gallate-Elicited Acid Sphingomyelinase Activation |
| title_full | Src Mediates Epigallocatechin-3-<i>O</i>-Gallate-Elicited Acid Sphingomyelinase Activation |
| title_fullStr | Src Mediates Epigallocatechin-3-<i>O</i>-Gallate-Elicited Acid Sphingomyelinase Activation |
| title_full_unstemmed | Src Mediates Epigallocatechin-3-<i>O</i>-Gallate-Elicited Acid Sphingomyelinase Activation |
| title_short | Src Mediates Epigallocatechin-3-<i>O</i>-Gallate-Elicited Acid Sphingomyelinase Activation |
| title_sort | src mediates epigallocatechin 3 i o i gallate elicited acid sphingomyelinase activation |
| topic | Src EGCG anticancer effect FAK sensing molecule 67LR |
| url | https://www.mdpi.com/1420-3049/25/22/5481 |
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