Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines.
Integrin-mediated adhesion influences cell survival and may prevent programmed cell death. Little is known about how drug-sensitive tumor cell lines survive initial exposures to cytotoxic drugs and eventually select for drug-resistant populations. Factors that allow for cell survival following acute cytotoxic drug exposure may differ from drug resistance mechanisms selected for by chronic drug exposure. We show here that drug-sensitive 8226 human myeloma cells, demonstrated to express both VLA-4 (alpha4beta1) and VLA-5 (alpha5beta1) integrin fibronectin (FN) receptors, are relatively resistant to the apoptotic effects of doxorubicin and melphalan when pre-adhered to FN and compared with cells grown in suspension. This cell adhesion mediated drug resistance, or CAM-DR, was not due to reduced drug accumulation or upregulation of anti-apoptotic Bcl-2 family members. As determined by flow cytometry, myeloma cell lines selected for drug resistance, with either doxorubicin or melphalan, overexpress VLA-4. Functional assays revealed a significant increase in alpha4-mediated cell adhesion in both drug-resistant variants compared with the drug-sensitive parent line. When removed from selection pressure, drug-resistant cell lines reverted to a drug sensitive and alpha4-low phenotype. Whether VLA-4-mediated FN adhesion offers a survival advantage over VLA-5-mediated adhesion remains to be determined. In conclusion, we have demonstrated that FN-mediated adhesion confers a survival advantage for myeloma cells acutely exposed to cytotoxic drugs by inhibiting drug-induced apoptosis. This finding may explain how some cells survive initial drug exposure and eventually express classical mechanisms of drug resistance such as MDR1 overexpression.
Damiano
J S
JS
H. Lee. Moffitt Cancer Center, University of South Florida, Tampa, FL; and the Arizona Cancer Center, University of Arizona, Tucson, AZ.
Cress
A E
AE
Hazlehurst
L A
LA
Shtil
A A
AA
Dalton
W S
WS
D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002448:Cell Adhesion / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005353:Fibronectins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016023:Integrins / Q000235:genetics*; D008558:Melphalan / Q000494:pharmacology; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005353:Fibronectins; D016023:Integrins; D004317:Doxorubicin; D008558:Melphalan