Major vault protein does not play a role in chemoresistance or drug localization in a non-small cell lung cancer cell line.
The human major vault protein (MVP) is the primary component of the 13 MDa vault complex. MVP has been implicated in the development of non-P-glycoprotein-mediated drug resistance in cancer cells. Here we present several lines of evidence that dispute this assertion. siRNAs capable of specifically and efficiently knocking down expression of MVP do not alter the ability of resistant cells to remove doxorubicin from the nucleus and do not increase sensitivity to the drug. Conversely, upregulation of MVP in chemosensitive cells does not confer increased drug resistance. In multi-drug resistant (MDR) lung carcinoma cells, fluorescence microscopy reveals that doxorubicin enters the nucleus and is then removed, inconsistent with suggestions that vaults either act to prevent the drug from entering the nucleus or are involved as a nuclear efflux pump. These data suggest that vaults play no direct role in the MDR phenotype in non-small cell lung carcinoma cells and that their cellular function remains unknown. These results also have important implications concerning the value of MVP as a drug target and as a prognostic marker for chemotherapy failure. Our results suggest the need for further investigation into the link between upregulation of vaults and malignancy, the mechanism behind non-P-gp-mediated drug resistance, and the role of vaults in human cells.
Huffman
Kenneth E
KE
Department of Pharmacology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9041, USA.
Corey
David R
DR
D001692:Biological Transport; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D004317:Doxorubicin / Q000378:metabolism* / Q000633:toxicity; D016503:Drug Delivery Systems / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D034741:RNA, Small Interfering / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D020394:Vault Ribonucleoprotein Particles / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000099187:Major Vault Protein
D004317:Doxorubicin; D034741:RNA, Small Interfering; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein