IAP family protein expression correlates with poor outcome of multiple myeloma patients in association with chemotherapy-induced overexpression of multidrug resistance genes.
Multidrug-resistant (MDR) multiple myeloma (MM) patients who fail chemotherapy frequently express MDR1 protein, which serves as an efflux pump that protects neoplastic cells. The expression of lung resistance protein (LRP), which mediates intercellular and nucleocytoplasmic transport, is also correlated with chemotherapy resistance and shorter survival of MM patients. Here, we investigated the chemotherapy-induced change of MDR expression in MM patients using quantitative RT-PCR. Overall expression levels of MDR1 and LRP in MM patients were significantly higher than those in control subjects and increased after chemotherapy. More than half of the patients exhibited increased expression of MDR1 (14/26) or LRP (17/26) after chemotherapy. Also, the expression of inhibitor of apoptosis proteins (IAP) was determined in association with the prognosis of the patients. Among patients with increased MDR1-expression after chemotherapy, those with a poor outcome exhibited significant increases in survivin, cIAP1, cIAP2, and XIAP expression by chemotherapy compared with those with a good prognosis. Similarly, in the LRP expression-increased group, patients with a poor outcome showed significant increases of cIAP1 and cIAP2 expression compared with those with longer survival. In patients with reduced-MDR1 or LRP expression after chemotherapy, changes in the expression of IAPs induced by chemotherapy did not correlate with their prognosis. These findings indicate that IAP family proteins might play a role in worsening the prognosis of MM patients in association with chemotherapy-induced overexpression of MDR1 or LRP.
Nakagawa
Yasunori
Y
Department of Comprehensive Pathology, Aging and Developmental Sciences, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Abe
Shinya
S
Kurata
Morito
M
Hasegawa
Maki
M
Yamamoto
Kouhei
K
Inoue
Miori
M
Takemura
Tamiko
T
Suzuki
Kenshi
K
Kitagawa
Masanobu
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001483:Base Sequence; D001853:Bone Marrow / Q000503:physiopathology; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers; D018432:Drug Resistance, Multiple; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D017931:DNA Primers; D051034:Inhibitor of Apoptosis Proteins; D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C494833:BIRC2 protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases