Bcr-Abl-independent mechanism of resistance to imatinib in K562 cells: Induction of cyclooxygenase-2 (COX-2) by histone deacetylases (HDACs).
Our previous studies have shown that overexpression of MDR1 and cyclooygenase-2 (COX-2) resulted in resistance development to imatinib in chronic myelogenous leukemia (CML) K562 (IR-K562) cells. In the present study, the regulatory mechanism of MDR1 induction by COX-2 was investigated. A gradual overexpression of MDR1 and COX-2 during the process of development was observed. Furthermore, down regulation of MDR1 upon COX-2 knockdown by siRNA showed a decrease in the PKC levels and activation of PKC by addition of PGE(2) to K562 cells, suggesting a role for PKC in the COX-2 mediated induction of MDR1. The present study demonstrates COX-2 induction by HDACs and MDR1 induction by COX-2 via PGE(2)-cAMP-PKC-mediated pathway.
Kalle
Arunasree M
AM
Institute of Life Sciences, University of Hyderabad Campus, 500046 Hyderabad, A.P., India. arunasreemk@ilsresearch.org
Sachchidanand
Sachchidanand
S
Pallu
Reddanna
R
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001483:Base Sequence; D001549:Benzamides; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001549:Benzamides; D017931:DNA Primers; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; D051546:Cyclooxygenase 2; D016044:Fusion Proteins, bcr-abl; D011493:Protein Kinase C; D006655:Histone Deacetylases