Inhibition of focal adhesion kinase by antisense oligonucleotides enhances the sensitivity of breast cancer cells to camptothecins.
This study shows a strong association between cell attachment to substratum and activation of beta 1-integrin-signaling with resistance to the camptothecin derivative topotecan (TPT) in breast cancer cells. We propose a mechanistic-driven approach to sensitize the cells to camptothecins. ZR-75-1 anchorage-dependent breast cancer cell line, its derivative 9D3S suspension cells (9D3S-S), and 9D3S cells attached to fibronectin-coated plates (9D3S-A) were treated with TPT (1 microM) or CPT-11 (40 microM) for 48 h. Programmed cell death (PCD), as shown by poly(ADP-ribose) polymerase (PARP), pro-caspase-3 and pro-caspase-9 cleavage, was observed in 9D3S-S cells but not in ZR-75-1 or 9D3S-A cells. Because p125 focal adhesion kinase (FAK) is a transducer in the beta 1-integrin signaling pathway, it is essential to cell adhesion and it is overexpressed in metastatic breast cancer, we hypothesized that attenuation of FAK might enhance the sensitivity of breast cancer cells to camptothecins. Moreover, inhibition of FAK gene expression by a phosphorothioated antisense oligodeoxynucleotide targeting the portion of the gene encoding amino acids 262-268, increased the sensitivity of ZR-75-1, MDA-MB-231 and MCF7 breast cancer cells to treatment with TPT or CPT-11.
Satoh
Taroh H
TH
School of Natural and Health Sciences, Barry University, 11300 N.E. Second Ave., Miami Shores, FL 33161, USA.
Surmacz
Tatiana A
TA
Nyormoi
Okot
O
Whitacre
Cecilia M
CM
D000911:Antibodies, Monoclonal / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002166:Camptothecin / Q000627:therapeutic use*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012680:Sensitivity and Specificity; D019772:Topotecan / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D000090324:Tumor Protein, Translationally-Controlled 1
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004792:Enzyme Precursors; D005353:Fibronectins; D016376:Oligonucleotides, Antisense; D000090324:Tumor Protein, Translationally-Controlled 1; D019772:Topotecan; D011065:Poly(ADP-ribose) Polymerases; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D002166:Camptothecin