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: I-Hua Chen, Hsin-Chu Shih, Pei-Wen Hsieh, Fang-Rong Chang, Yang-Chang Wu, Chin-Chung Wu
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 289 Issue 2 Pg. 330-40 (Dec 01 2015) ISSN: 1096-0333 [Electronic] United States
• PMID: 26386190 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• 2-methoxy-4-(2-nitrovinyl)phenyl 2,3-dichlorobenzoate
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Chlorobenzoates
• Integrin beta1
• PXN protein, human
• Paxillin
• Protein Kinase Inhibitors
• Quinazolines
• Styrenes
• Tyrphostins
• RTKI cpd
• EGFR protein, human
• ErbB Receptors
• Focal Adhesion Kinase 1
• PTK2 protein, human
• src-Family Kinases

Topics

• Anoikis (drug effects)
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis Regulatory Proteins (metabolism)
• Breast Neoplasms (drug therapy, enzymology, pathology)
• Cell Adhesion (drug effects)
• Cell Aggregation (drug effects)
• Cell Line, Tumor
• Chlorobenzoates (pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Activation
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Female
• Focal Adhesion Kinase 1 (metabolism)
• Humans
• Integrin beta1 (metabolism)
• Paxillin (metabolism)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Quinazolines (pharmacology)
• Signal Transduction (drug effects)
• Styrenes (pharmacology)
• Tyrphostins (pharmacology)
• src-Family Kinases (metabolism)