S-phase kinase protein 2 is an attractive therapeutic target in a subset of diffuse large B-cell lymphoma.
S-phase kinase protein 2 (SKP2), an F-box protein, targets cell-cycle regulators including cycle-dependent kinase inhibitor p27KiP1 via ubiquitin-mediated degradation. SKP2 is frequently overexpressed in a variety of cancer cells and has been implicated in oncogenesis; however, its role in diffuse large B-cell lymphoma (DLBCL) has not been elucidated. Therefore, we investigated the role of SKP2 and its ubiquitin-proteasome pathway in a large series (301) of DLBCL patient samples and a panel of DLBCL cell lines. Using immunohistochemistry, SKP2 was detected in 41.6% of DLBCL tumours and was inversely associated with p27Kip1 protein level. The DLBCL subset with high SKP2 and low p27Kip1 showed a strong correlation with the proliferating index marker Ki-67 (p < 0.0001) and also with the germinal centre phenotype (p = 0.0147). Treatment of DLBCL cell lines with bortezomib or expression of SKP2-specific siRNA causes down-regulation of SKP2 and accumulation of p27Kip1, leading to suppression of growth by inducing apoptosis. Furthermore, treatment of DLBCL cells with bortezomib causes apoptosis via involving the mitochondrial pathway and activation of caspases. Finally, treatment of DLBCL cells with bortezomib down-regulated the expression of XIAP, cIAP1, and survivin. Altogether, these results suggest that SKP2 and the ubiquitin-proteasome pathway may be a potential target for therapeutic intervention in DLBCL.
Department of Human Cancer Genomic Research, Research Center, King Fahad National Center for Children's Cancer & Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
S
S
Uddin
A
A
Hussain
M
M
Ahmed
A
A
Belgaumi
F
F
Al-Dayel
D
D
Ajarim
P
P
Bavi
K S
KS
Al-Kuraya
D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011480:Protease Inhibitors / Q000627:therapeutic use; D011719:Pyrazines / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000494:pharmacology; D044786:S-Phase Kinase-Associated Proteins / Q000032:analysis / Q000235:genetics*
D001897:Boronic Acids; C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000069286:Bortezomib