Maximal apoptosis of renal cell carcinoma by the proteasome inhibitor bortezomib is nuclear factor-kappaB dependent.
Advanced renal cell carcinoma (RCC) is resistant to cytotoxic chemotherapy, and immunotherapy has modest activity. Proteasome inhibitors represent a novel class of anticancer agents that have activity across a wide spectrum of tumor types. We investigated the efficacy of the proteasome inhibitor bortezomib (VELCADE, formerly known as PS-341) in RCC and found that bortezomib potently induces apoptosis of RCC cell lines. Blockade of the nuclear factor-kappaB (NF-kappaB) pathway is considered a crucial effect in bortezomib-induced apoptosis, but the dependence on NF-kappaB inhibition for bortezomib-mediated death has not been formally demonstrated. Thus, we also studied the contribution of NF-kappaB inhibition as a mechanism of bortezomib-induced apoptosis in RCC cells, which display constitutive NF-kappaB activation. Ectopic expression of the NF-kappaB family members, p65 (Rel A) and p50 (NF-kappaB1), markedly reduced bortezomib-induced apoptosis. However, when we used selective genetic and chemical inhibitors of NF-kappaB, we found that NF-kappaB blockade was not sufficient to induce apoptosis of RCC cells. Thus, we conclude that maximal bortezomib-induced apoptosis is dependent on its NF-kappaB inhibitory effect, but NF-kappaB-independent effects also play a critical role in the induction of apoptosis by bortezomib. This represents the first report to formally demonstrate that bortezomib-induced NF-kappaB blockade is required to achieve the maximum degree of apoptosis by this drug.
An
Jiabin
J
VA Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Building 304, Room E1-113, Los Angeles, CA 90073, USA.
Sun
Yiping
Y
Fisher
Myrna
M
Rettig
Matthew B
MB
D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*
D001897:Boronic Acids; D016328:NF-kappa B; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex