Bortezomib inhibits docetaxel-induced apoptosis via a p21-dependent mechanism in human prostate cancer cells

Abstract

Bortezomib (PS-341, Velcade) is a peptide boronate inhibitor of the 20S proteasome that is currently being combined with taxanes in several clinical trials in patients with prostate cancer. Here, we report that bortezomib inhibited docetaxel-induced M-phase arrest and apoptosis in androgen-dependent LNCaP-Pro5 cells. Direct analysis of kinase activity in immune complex kinase assays revealed that docetaxel activated cyclin-dependent kinase (CDK) 1 (CDC2) and that bortezomib blocked this activation. The effects of bortezomib were associated with accumulation of p21 and mimicked by chemical CDK inhibitors or by transfecting cells with a small interfering RNA construct specific for CDK1. Transient transfection with p21 also inhibited docetaxel-induced apoptosis; conversely, p21 silencing reversed the antagonistic effects of bortezomib on docetaxel-induced apoptosis. Together, our data show that bortezomib interferes with docetaxel-induced apoptosis via a p21-dependent mechanism that is associated with CDK1 inhibition. These observations may have important implications for the ongoing bortezomib-docetaxel combination trials as well as trials using bortezomib and other cell cycle -sensitive agents.

BCL-2 family regulation by the 20S proteasome inhibitor bortezomib

“…However, a recent phase II trial randomizing patients to bortezomib alone or docetaxel and bortezomib, demonstrated only minor evidence of enhancement in clinical outcome (Fanucchi et al, 2006), suggesting that other determinants of sensitivity or resistance to bortezomib and docetaxel are likely to be relevant in this disease setting. One relevant factor, for example, may be bortezomib-mediated p21-dependent antagonism of docetaxel that has been reported in prostate cancer cells (Canfield et al, 2006).…”

“…BAK is guarded from its activator BH3 proteins by MCL-1 (along with BCL-X L ), which directly sequesters tBID (Clohessy et al, 2006) and BIM (Gomez-Bougie et al, 2005) but also binds BAK directly, inhibiting its activation until released by free BH3-only proteins (Chen et al, 2005). The binding of tBID by MCL-1 may account for the mechanism underlying its ability to confer resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL; Henson et al, 2003;Taniai et al, 2004;Canfield et al, 2006). MCL-1 is targeted for polyubiquitination and proteasome-mediated degradation following DNA damage by the BH3-only protein MULE-1/ARF/LASU1 (Nijhawan et al, 2003;Warr et al, 2005;Zhong et al, 2005).…”

“…A second mechanism underlying proteasomal clearance of MCL-1 is associated with its phosphorylation by the AKT substrate, glycogen synthase kinase 3, on a conserved serine site, S159 (Maurer et al, 2006). Finally, granzyme B or activation of caspases 3 and 7, for example by TRAIL directly degrades MCL-1 resulting in the disruption of its interaction with BIM, freeing BIM to engage with BAX (Han et al, 2004;Herrant et al, 2004;Annis et al, 2005;Canfield et al, 2006).…”

Assessment of apoptosis-inducing effects of docetaxel combined with the proteasome inhibitor PS-341 in human lung cancer cells

“…13,14 Given this mechanism, the combination of PS-341 and DTX as a cancer therapeutic regimen was evaluated in some preclinical and clinical studies. [15][16][17][18][19] However, the preclinical studies generated mixed outcomes showing that PS-341 can either enhance or antagonize DTX-induced apoptosis or antitumor activity depending on cell lines or models. 15,17 Moreover, it has been shown that the impact of PS-341 on chemotherapy (incuding DTX)-induced apoptosis or anticancer activity is sequence-or schedule-dependent.…”

“…[15][16][17][18][19] However, the preclinical studies generated mixed outcomes showing that PS-341 can either enhance or antagonize DTX-induced apoptosis or antitumor activity depending on cell lines or models. 15,17 Moreover, it has been shown that the impact of PS-341 on chemotherapy (incuding DTX)-induced apoptosis or anticancer activity is sequence-or schedule-dependent. 20,21 Thus, it is necessary to perform preclinical studies to carefully evaluate the efficacy of the PS-341 and DTX combination in various types of cancer to avoid a harmful combination outcome.…”