Proteasome inhibitor MG-132 mediated expression of p27Kip1 via S-phase kinase protein 2 degradation induces cell cycle coupled apoptosis in primary effusion lymphoma cells.
Primary effusion lymphoma (PEL) is an incurable, aggressive B-cell malignancy that develops rapid resistance to conventional chemotherapy. MG-132, a proteasome inhibitor, suppresses cell proliferation and induces apoptosis in several PEL cell lines. Treatment of PEL cells with MG-132 results in downregulation of S-phase kinase protein 2 (SKP2) and accumulation of p27Kip1. Furthermore, MG-132 treatment of PEL cells causes Bax conformational changes, leading to loss of mitochondrial membrane potential and release of cytochrome c to the cytosole. Such cytochrome c release results in sequential activation of caspases and apoptosis, while pretreatment of PEL cells with universal inhibitor of caspases, z-VAD-fmk prevents cell death induced by MG-132. Finally, our data demonstrated in PEL cells that MG-132 downregulates the expression of inhibitor of apoptosis proteins XIAP, cIAP1 and survivin. Altogether, these findings suggest that MG-132 is a potent inducer of apoptosis of PEL cells via downregulation of SKP2 leading to accumulation of p27Kip1, resulting in cell cycle arrest and apoptosis and strongly suggest that targeting the proteasomal pathway may provide a novel therapeutic approach for the treatment of PEL.
Hussain
Azhar R
AR
Human Cancer Genomic Research, King Fahad National Children's Cancer Center, Riyadh, Saudi Arabia.
Ahmed
Maqbool
M
Ahmed
Saeeda O
SO
Al-Thari
Sara
S
Khan
Asma S
AS
Razack
Shirin
S
Platanias
Leonidas C
LC
Al-Kuraya
Khawla S
KS
Uddin
Shahab
S
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D007976:Leupeptins / Q000494:pharmacology*; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis
D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D007976:Leupeptins; D008869:Microtubule-Associated Proteins; D044786:S-Phase Kinase-Associated Proteins; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D050760:Cyclin-Dependent Kinase Inhibitor p27; D045304:Cytochromes c; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde