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Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant.
Oncogene. 2002 Aug 01; 21(33):5160-74.O

Abstract

We report here that expression of proteinase 3 (PR3), a serine protease, is down-regulated in the HL60/ADR multidrug resistant variant of the human myelogenous leukemia cell line HL-60, and that down-regulation of PR3 is associated with doxorubicin (DOX) resistance in these cells. To determine whether PR3 is involved in DOX-induced apoptosis in HL-60 cells, and whether its loss causes resistance to DOX, we inhibited PR3 expression by an anti-sense PR3 oligodeoxynucleotide and showed that inhibition of PR3 expression results in a significant reduction in DOX-induced DNA fragmentation and increased resistance to DOX-induced apoptosis. Our results revealed that PR3-mediated DOX-induced apoptosis in HL-60 cells is independent of the loss of mitochondrial membrane potential (deltapsi(m)) and activation of the caspase-8 and -9 pathways. Moreover, while PR3 is involved in the cleavage of caspase-3, PR3-mediated DOX-induced DNA fragmentation and apoptosis were not prevented by a specific inhibitor of caspase-3. These data suggest that activation of caspase-3 alone is not sufficient to trigger PR3-mediated DOX-induced apoptosis. Treatment with an anti-PR3 oligomer significantly decreased reactive oxygen species (ROS) generation in cells treated with low concentrations of DOX, revealing a role for PR3 in enhancing production of DOX-induced ROS. Moreover, DOX-induced apoptosis at 0.001-0.01 microM was only inhibited in HL-60 cells pre-treated with the antioxidant N-acetyl-cysteine in the absence of anti-PR3, revealing that DOX-induced apoptosis in these cells is PR3- and ROS-dependent. Our results show that PR3 is involved in DOX-induced ROS-dependent apoptosis and that its loss is associated with resistance to DOX in HL-60 cells.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Indiana University, 1044 West Walnut R4-119, Indianapolis, Indiana, IN 46202, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12140766

Citation

Wu, Ching-Huang, et al. "Proteinase-3, a Serine Protease Which Mediates Doxorubicin-induced Apoptosis in the HL-60 Leukemia Cell Line, Is Downregulated in Its Doxorubicin-resistant Variant." Oncogene, vol. 21, no. 33, 2002, pp. 5160-74.
Wu CH, Gordon J, Rastegar M, et al. Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant. Oncogene. 2002;21(33):5160-74.
Wu, C. H., Gordon, J., Rastegar, M., Ogretmen, B., & Safa, A. R. (2002). Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant. Oncogene, 21(33), 5160-74.
Wu CH, et al. Proteinase-3, a Serine Protease Which Mediates Doxorubicin-induced Apoptosis in the HL-60 Leukemia Cell Line, Is Downregulated in Its Doxorubicin-resistant Variant. Oncogene. 2002 Aug 1;21(33):5160-74. PubMed PMID: 12140766.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant. AU - Wu,Ching-Huang, AU - Gordon,John, AU - Rastegar,Mojgan, AU - Ogretmen,Besim, AU - Safa,Ahmad R, PY - 2002/01/23/received PY - 2002/04/19/revised PY - 2002/04/24/accepted PY - 2002/7/26/pubmed PY - 2002/8/17/medline PY - 2002/7/26/entrez SP - 5160 EP - 74 JF - Oncogene JO - Oncogene VL - 21 IS - 33 N2 - We report here that expression of proteinase 3 (PR3), a serine protease, is down-regulated in the HL60/ADR multidrug resistant variant of the human myelogenous leukemia cell line HL-60, and that down-regulation of PR3 is associated with doxorubicin (DOX) resistance in these cells. To determine whether PR3 is involved in DOX-induced apoptosis in HL-60 cells, and whether its loss causes resistance to DOX, we inhibited PR3 expression by an anti-sense PR3 oligodeoxynucleotide and showed that inhibition of PR3 expression results in a significant reduction in DOX-induced DNA fragmentation and increased resistance to DOX-induced apoptosis. Our results revealed that PR3-mediated DOX-induced apoptosis in HL-60 cells is independent of the loss of mitochondrial membrane potential (deltapsi(m)) and activation of the caspase-8 and -9 pathways. Moreover, while PR3 is involved in the cleavage of caspase-3, PR3-mediated DOX-induced DNA fragmentation and apoptosis were not prevented by a specific inhibitor of caspase-3. These data suggest that activation of caspase-3 alone is not sufficient to trigger PR3-mediated DOX-induced apoptosis. Treatment with an anti-PR3 oligomer significantly decreased reactive oxygen species (ROS) generation in cells treated with low concentrations of DOX, revealing a role for PR3 in enhancing production of DOX-induced ROS. Moreover, DOX-induced apoptosis at 0.001-0.01 microM was only inhibited in HL-60 cells pre-treated with the antioxidant N-acetyl-cysteine in the absence of anti-PR3, revealing that DOX-induced apoptosis in these cells is PR3- and ROS-dependent. Our results show that PR3 is involved in DOX-induced ROS-dependent apoptosis and that its loss is associated with resistance to DOX in HL-60 cells. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/12140766/Proteinase_3_a_serine_protease_which_mediates_doxorubicin_induced_apoptosis_in_the_HL_60_leukemia_cell_line_is_downregulated_in_its_doxorubicin_resistant_variant_ L2 - https://doi.org/10.1038/sj.onc.1205639 DB - PRIME DP - Unbound Medicine ER -