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The Scientific World Journal
Volume 2014 (2014), Article ID 902987, 8 pages
http://dx.doi.org/10.1155/2014/902987
Research Article

RHBDL2 Is a Critical Membrane Protease for Anoikis Resistance in Human Malignant Epithelial Cells

1Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
2Cardiovascular Research Center, National Cheng Kung University, Tainan 701, Taiwan
3Department of Biochemistry, College of Medicine, Tzu Chi University, Hualien 970, Taiwan
4Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan 717, Taiwan
5Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
6Center for Bioscience and Biotechnology, National Cheng Kung University, Tainan 701, Taiwan

Received 10 February 2014; Revised 14 April 2014; Accepted 11 May 2014; Published 28 May 2014

Academic Editor: Luca Scorrano

Copyright © 2014 Tsung-Lin Cheng et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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.