Rad knockdown induces mitochondrial apoptosis in bortezomib resistant leukemia and lymphoma cells.
To understand the molecular mechanism(s) underlying bortezomib resistance, we sought to identify potential target genes that were differentially expressed in bortezomib-resistant leukemia cells versus parental controls. Microarray analysis revealed that the mRNA levels of Rad (Ras associated with diabetes) were higher in the bortezomib-resistant Jurkat (Jurkat-R) cells than in the parental control cells. The importance of Rad for bortezomib resistance was supported by three observations. First, Rad knockdown overcame bortezomib resistance and induced mitochondrial apoptosis via Noxa/Bcl-2 modulation. Second, Rad decreased cell death in response to bortezomib. Third, leukemia and lymphoma cell lines (K-562, Raji, IM-9 and Jurkat-R) with elevated Rad expression levels showed higher degrees of bortezomib resistance versus those (Sup-B15, JVM-2, U266 and Jurkat) with low Rad expression levels (r=0.48, P=0.0004). Thus, Rad over expression could be a molecular target to improve bortezomib sensitivity in human leukemia and lymphoma.
Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea.
Seon-Yong
SY
Yeom
Sook-Ja
SJ
Lee
Won Seog
WS
Kim
Chaehwa
C
Park
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D011719:Pyrazines / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D034741:RNA, Small Interfering; C084355:RRAD protein, human; D000069286:Bortezomib; D018631:ras Proteins