Mechanisms underlying lung resistance-related protein (LRP)-mediated doxorubicin resistance of non-small cell lung cancer cells.
Lung resistance-related protein (LRP) is a human major vault protein (MVP) implicated in drug
resistance of cancer cells in a cell-type dependent manner. The primary goal of the study was to understand the
role(s) of LRP in doxorubicin (DOX) resistance of non-small cell lung cancer (NSCLC) cells and the
underlying working mechanisms. In the study, the roles of LRP in the regulation of DOX dynamics, nuclear
import of minor vault proteins (vault poly (ADP-ribose) polymerase, vPARP and telomerase
associated protein-1, TEP-1) and DOX-mediated cytotoxicity were examined in CH27
and H460 cells. Our results were the first to show that the CH27 cells with higher LRP expression
levels were more resistant to DOX-induced cytotoxicity as shown in apoptosis experiments. LRP at the
nuclear membrane could regulate DOX efflux from the nucleus to the cytosol, and also the reverse
vPARP/TEP1 influx from the cytosol, to protect NSCLC cells from DOX-induced apoptosis. Cytosolic
LRP could bind to DOX, vPARP and TEP1 to clear DOX away from the nucleus and promote the assembly
of vaults for cell protection again. Based on the data obtained, the molecular mechanisms responsible for
DOX resistance of NSCLC were delineated to demonstrate that LRP, vPARP and TEP1 were potential
targets for NSCLC therapy. Inhibitors of these proteins, including small interfering LRP (siLRP), wheat-germ
agglutenin (WGA) (WGA), 3-aminobenzamide (3-AB) and 3,6,9-trisubstituted acridine 9-[4-(N,N-dimethylamino)
phenylamino]-3,6-bis(3-pyrrolodinopropionamido) acridine (BRACO-19), break down the DOX resistance of NSCLC cells, particularly in CH27 cells, and may have therapeutic values in the control of NSCLC.
Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan, Republic of China.
Yu-Lun
YL
Chen
Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan, Republic of China.
Tsung-Ying
TY
Yang
Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan, Republic of China.|Center for Quality Management, Taichung Veterans General Hospital, Taichung 40705, Taiwan, Republic of China.
Chieh-Liang
CL
Wu
Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan, Republic of China.
Kun-Chieh
KC
Chen
Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan, Republic of China.|Department of Education and Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan, Republic of China.
Shih-Lan
SL
Hsu
Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan, Republic of China.|Agricultural Biotechnology Center, National Chung Hsing University, Taichung 40227, Taiwan, Republic of China.
Chi-Mei
CM
Hsueh
D000903:Antibiotics, Antineoplastic; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016601:RNA-Binding Proteins; D020394:Vault Ribonucleoprotein Particles / Q000378:metabolism*; D000099187:Major Vault Protein
D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases; D016601:RNA-Binding Proteins; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C104342:TEP1 protein, human; C449359:vault poly(ADP-ribose) polymerase
NSCLC; LRP; vPARP; TEP1; DOX resistance