Noxa/Mcl-1 balance influences the effect of the proteasome inhibitor MG-132 in combination with anticancer agents in pancreatic cancer cell lines

Abstract

Pancreatic cancer progresses aggressively and owing to chemoresistance responds poorly to chemotherapy. Thus, there is an urgent need to understand the mechanisms of cancer cell resistance to generate effective strategies to circumvent intrinsic chemoresistance in this tumour indication. In this study, three pancreatic cancer cell lines, MIA PaCa-2, MDAPanc-3 and AsPC-1, were treated with the proteasome inhibitor MG-132 together with camptothecin, doxorubicin or paclitaxel, and cytotoxicity was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The combination of MG-132 and camptothecin at a ratio of 5 : 1 gave the most promising results and enhanced cytotoxicity compared with the single compounds in MIA PaCa-2 cells. The increase was shown to be due to enhanced caspase-3 activity resulting in apoptosis. Moreover, this combination upregulated the levels of the proapoptotic protein Noxa and reduced the levels of the antiapoptotic protein Mcl-1, as demonstrated by western blotting. In contrast, the combination of MG-132 with doxorubicin also induced increased cytotoxicity, but apoptosis was decreased. The lack of an enhanced apoptosis induction could be correlated with high levels of Mcl-1 in response to the combined treatment with MG-132 and doxorubicin. Thus, the results indicate that regulation of the antiapoptotic and proapoptotic Bcl-2 family members Noxa and Mcl-1 is predicative of the effectiveness of the combination of MG-132 with different anticancer agents on apoptosis induction in pancreatic cancer cells.

Cisplatin Hypersensitivity of Testicular Germ Cell Tumors Is Determined by High Constitutive Noxa Levels Mediated by Oct-4

“…2A), enforcing a higher apoptotic threshold. A similar dependence on the Noxa/ Mcl-1 balance was shown for HeLa and pancreatic cancer cells treated with camptothecin (37,38). It is of note that Noxa was recently shown to be capable of binding Bcl-xL upon DNA damage and thus facilitate apoptosis induction (39), a conceivable mechanism that broadens the proapoptotic capacity of Noxa.…”

The cyclin-dependent kinase inhibitor SNS-032 induces apoptosis in breast cancer cells via depletion of Mcl-1 and X-linked inhibitor of apoptosis protein and displays antitumor activity in vivo

“…Mcl-1, an antiapoptotic member of the Bcl-2 family, is among the most frequently amplified genes in human cancer and is essential for the survival of carcinoma cells. Mcl-1 is thought to act by antagonizing pro-apoptotic proteins such as Bim (40). XIAP is a member of the IAP family and plays a key role in cell survival.…”

Positioning of proteasome inhibitors in therapy of solid malignancies

“…Whereas a combination of MG132 and doxorubicin was antagonistic, MG-132 and camptothecin proved synergistic in inducing apoptosis. The latter was confirmed by reduced levels of Mcl-1 protein, an anti-apoptotic protein, and enhanced levels of the pro-apoptotic protein Noxa were found with this combined treatment [ 104 ]. The balance of Noxa and Mcl-1 appeared a good indicator for PI-induced apoptosis and could predict the effectivity of PIs in pancreatic cancer cells [ 104 ].…”

“…The latter was confirmed by reduced levels of Mcl-1 protein, an anti-apoptotic protein, and enhanced levels of the pro-apoptotic protein Noxa were found with this combined treatment [ 104 ]. The balance of Noxa and Mcl-1 appeared a good indicator for PI-induced apoptosis and could predict the effectivity of PIs in pancreatic cancer cells [ 104 ]. Another study showed that BTZ-induced apoptosis in pancreatic cancer cells is associated with the increased production of ceramide lipids [ 105 ].…”

“…A study by Nauman et al investigated the cytotoxic effects of the PI MG-132 as single agents and in combination with various conventional chemotherapeutics in pancreatic cancer cell lines [ 104 ]. Whereas a combination of MG132 and doxorubicin was antagonistic, MG-132 and camptothecin proved synergistic in inducing apoptosis.…”