RHBDL2 Is a Critical Membrane Protease for Anoikis Resistance in Human Malignant Epithelial Cells
Anoikis resistance allows metastatic tumor cells to survive in a homeless environment. Activation of epithelial growth factor receptor (EGFR) signaling is one of the key mechanisms for metastatic tumor cells to resist anoikis, yet the regulation mechanisms of homeless-triggered EGFR activation in me...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2014-01-01
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| Series: | The Scientific World Journal |
| Online Access: | http://dx.doi.org/10.1155/2014/902987 |
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| author | Tsung-Lin Cheng Chao-Han Lai Shinn-Jong Jiang Jui-Hsiang Hung Shi-Kai Liu Bi-Ing Chang Guey-Yueh Shi Hua-Lin Wu |
| author_facet | Tsung-Lin Cheng Chao-Han Lai Shinn-Jong Jiang Jui-Hsiang Hung Shi-Kai Liu Bi-Ing Chang Guey-Yueh Shi Hua-Lin Wu |
| author_sort | Tsung-Lin Cheng |
| collection | DOAJ |
| description | Anoikis resistance allows metastatic tumor cells to survive in a homeless environment. Activation of epithelial growth factor receptor (EGFR) signaling is one of the key mechanisms for metastatic tumor cells to resist anoikis, yet the regulation mechanisms of homeless-triggered EGFR activation in metastatic tumor cells remain unclear. Rhomboid-like-2 (RHBDL2), an evolutionally conserved intramembrane serine protease, can cleave the EGF ligand and thus trigger EGFR activation. Herein, we demonstrated that RHBDL2 overexpression in human epithelial cells resulted in promotion of cell proliferation, reduction of cell adhesion, and suppression of anoikis. During long-term suspension cultures, increased RHBDL2 was only detected in aggressive tumor cell lines. Treatment with the rhomboid protease inhibitor or RHBDL2 shRNA increased cleaved caspase 3, a marker of apoptosis. Finally, inhibition of EGFR activation increased the cleaved caspase 3 and attenuated the detachment-induced focal adhesion kinase phosphorylation. Taken together, these findings provide evidence for the first time that RHBDL2 is a critical molecule in anoikis resistance of malignant epithelial cells, possibly through the EGFR-mediated signaling. Our study demonstrates RHBDL2 as a new therapeutic target for cancer metastasis. |
| format | Article |
| id | doaj-art-435b8a5c33964d7c8a28b5aaff3963a5 |
| institution | OA Journals |
| issn | 2356-6140 1537-744X |
| language | English |
| publishDate | 2014-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | The Scientific World Journal |
| spelling | doaj-art-435b8a5c33964d7c8a28b5aaff3963a52025-08-20T02:37:58ZengWileyThe Scientific World Journal2356-61401537-744X2014-01-01201410.1155/2014/902987902987RHBDL2 Is a Critical Membrane Protease for Anoikis Resistance in Human Malignant Epithelial CellsTsung-Lin Cheng0Chao-Han Lai1Shinn-Jong Jiang2Jui-Hsiang Hung3Shi-Kai Liu4Bi-Ing Chang5Guey-Yueh Shi6Hua-Lin Wu7Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, TaiwanCardiovascular Research Center, National Cheng Kung University, Tainan 701, TaiwanDepartment of Biochemistry, College of Medicine, Tzu Chi University, Hualien 970, TaiwanBiotechnology, Chia-Nan University of Pharmacy and Science, Tainan 717, TaiwanCardiovascular Research Center, National Cheng Kung University, Tainan 701, TaiwanCardiovascular Research Center, National Cheng Kung University, Tainan 701, TaiwanCardiovascular Research Center, National Cheng Kung University, Tainan 701, TaiwanCardiovascular Research Center, National Cheng Kung University, Tainan 701, TaiwanAnoikis resistance allows metastatic tumor cells to survive in a homeless environment. Activation of epithelial growth factor receptor (EGFR) signaling is one of the key mechanisms for metastatic tumor cells to resist anoikis, yet the regulation mechanisms of homeless-triggered EGFR activation in metastatic tumor cells remain unclear. Rhomboid-like-2 (RHBDL2), an evolutionally conserved intramembrane serine protease, can cleave the EGF ligand and thus trigger EGFR activation. Herein, we demonstrated that RHBDL2 overexpression in human epithelial cells resulted in promotion of cell proliferation, reduction of cell adhesion, and suppression of anoikis. During long-term suspension cultures, increased RHBDL2 was only detected in aggressive tumor cell lines. Treatment with the rhomboid protease inhibitor or RHBDL2 shRNA increased cleaved caspase 3, a marker of apoptosis. Finally, inhibition of EGFR activation increased the cleaved caspase 3 and attenuated the detachment-induced focal adhesion kinase phosphorylation. Taken together, these findings provide evidence for the first time that RHBDL2 is a critical molecule in anoikis resistance of malignant epithelial cells, possibly through the EGFR-mediated signaling. Our study demonstrates RHBDL2 as a new therapeutic target for cancer metastasis.http://dx.doi.org/10.1155/2014/902987 |
| spellingShingle | Tsung-Lin Cheng Chao-Han Lai Shinn-Jong Jiang Jui-Hsiang Hung Shi-Kai Liu Bi-Ing Chang Guey-Yueh Shi Hua-Lin Wu RHBDL2 Is a Critical Membrane Protease for Anoikis Resistance in Human Malignant Epithelial Cells The Scientific World Journal |
| title | RHBDL2 Is a Critical Membrane Protease for Anoikis Resistance in Human Malignant Epithelial Cells |
| title_full | RHBDL2 Is a Critical Membrane Protease for Anoikis Resistance in Human Malignant Epithelial Cells |
| title_fullStr | RHBDL2 Is a Critical Membrane Protease for Anoikis Resistance in Human Malignant Epithelial Cells |
| title_full_unstemmed | RHBDL2 Is a Critical Membrane Protease for Anoikis Resistance in Human Malignant Epithelial Cells |
| title_short | RHBDL2 Is a Critical Membrane Protease for Anoikis Resistance in Human Malignant Epithelial Cells |
| title_sort | rhbdl2 is a critical membrane protease for anoikis resistance in human malignant epithelial cells |
| url | http://dx.doi.org/10.1155/2014/902987 |
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