title: HPW-RX40 restores anoikis sensitivity of human breast cancer cells by inhibiting integrin/FAK signaling.
abstract: Anoikis is defined as apoptosis, which is induced by inappropriate cell-matrix interactions. Cancer cells with anoikis resistance tend to undergo metastasis, and this phenomenon has been reported to be associated with integrin and FAK activity. HPW-RX40 is a derivative of 3,4-methylenedioxy-β-nitrostyrene, which is known to prevent platelet aggregation by inhibition of integrin. In the present study, we investigated the effect of HPW-RX40 on an anoikis-resistant human breast cancer cell line MDA-MB-231. HPW-RX40 inhibited cell aggregation and induced cell death in suspending MDA-MB-231 cells, but had only little effect on the monolayer growth of adherent cells. Analysis of caspase activation and poly (ADP-ribose) polymerase (PARP) cleavage confirmed anoikis in HPW-RX40-treated suspending cancer cells. HPW-RX40 also affected the Bcl-2 family proteins in detached cancer cells. Furthermore, HPW-RX40 inhibited detachment-induced activation of FAK and the downstream phosphorylation of Src and paxillin, but did not affect this pathway in adherent cancer cells. We also found that the expression and activation of β1 integrin in MDA-MB-231 cells were reduced by HPW-RX40. The combination of HPW-RX40 with an EGFR inhibitor led to enhanced anoikis and inhibition of the FAK pathway in breast cancer cells. Taken together, our results suggest that HPW-RX40 restores the anoikis sensitivity in the metastatic breast cancer cells by inhibiting integrin and subsequent FAK activation, and reveal a potential strategy for prevention of tumor metastasis.
authors.affiliation: Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: I-Hua
authors.initials: IH
authors.lastname: Chen
authors.affiliation: Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Hsin-Chu
authors.initials: HC
authors.lastname: Shih
authors.affiliation: Graduate Institute of Natural Products, School of Traditional Chinese Medicine, and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Fang-Rong
authors.initials: FR
authors.lastname: Chang
authors.affiliation: School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan. Electronic address: yachwu@mail.cmu.edu.
authors.forename: Yang-Chang
authors.initials: YC
authors.lastname: Wu
authors.affiliation: Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80708, Taiwan; Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: ccwu@kmu.edu.tw.
authors.forename: Chin-Chung
authors.initials: CC
authors.lastname: Wu
mesh_terms: D023102:Anoikis / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002449:Cell Aggregation / Q000187:drug effects; D045744:Cell Line, Tumor; D002723:Chlorobenzoates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013343:Styrenes / Q000494:pharmacology*; D020032:Tyrphostins / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C000605642:2-methoxy-4-(2-nitrovinyl)phenyl 2,3-dichlorobenzoate; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002723:Chlorobenzoates; D019012:Integrin beta1; C496061:PXN protein, human; D051419:Paxillin; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013343:Styrenes; D020032:Tyrphostins; C101044:RTKI cpd; C512478:EGFR protein, human; D066246:ErbB Receptors; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases
keywords: Anoikis; Breast cancer; FAK; Integrin; Metastasis; β-Nitrostyrene