title: RHBDL2 is a critical membrane protease for anoikis resistance in human malignant epithelial cells.
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.
authors: Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors: Tsung-Lin
authors: 0000-0001-7080-8652
authors: TL
authors: Cheng
authors: Cardiovascular Research Center, National Cheng Kung University, Tainan 701, Taiwan.
authors: Chao-Han
authors: CH
authors: Lai
authors: Department of Biochemistry, College of Medicine, Tzu Chi University, Hualien 970, Taiwan.
authors: Shinn-Jong
authors: SJ
authors: Jiang
authors: Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan 717, Taiwan.
authors: Jui-Hsiang
authors: JH
authors: Hung
authors: Cardiovascular Research Center, National Cheng Kung University, Tainan 701, Taiwan.
authors: Shi-Kai
authors: 0000-0002-9571-0042
authors: SK
authors: Liu
authors: Cardiovascular Research Center, National Cheng Kung University, Tainan 701, Taiwan.
authors: Bi-Ing
authors: BI
authors: Chang
authors: Cardiovascular Research Center, National Cheng Kung University, Tainan 701, Taiwan ; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors: Guey-Yueh
authors: GY
authors: Shi
authors: Cardiovascular Research Center, National Cheng Kung University, Tainan 701, Taiwan ; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan ; Center for Bioscience and Biotechnology, National Cheng Kung University, Tainan 701, Taiwan.
authors: Hua-Lin
authors: HL
authors: Wu
mesh_terms: D023102:Anoikis; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000473:pathology*; D012697:Serine Endopeptidases; D057057:Serine Proteases / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D057057:Serine Proteases; D012697:Serine Endopeptidases; C545655:RHBDL2 protein, human