Ubiquitin-Proteasome System Stress Sensitizes Ovarian Cancer to Proteasome Inhibitor–Induced Apoptosis

Abstract

The ubiquitin-proteasome system (UPS) mediates targeted protein degradation. Notably, the UPS determines levels of key checkpoint proteins controlling apoptosis and proliferation by controlling protein half-life. Herein, we show that ovarian carcinoma manifests an overstressed UPS by comparison with normal tissues by accumulation of ubiquitinated proteins despite elevated proteasome levels. Elevated levels of total ubiquitinated proteins and 19S and 20S proteasome subunits are evident in both low-grade and high-grade ovarian carcinoma tissues relative to benign ovarian tumors and in ovarian carcinoma cell lines relative to immortalized surface epithelium. We find that ovarian carcinoma cell lines exhibit greater sensitivity to apoptosis in response to proteasome inhibitors than immortalized ovarian surface epithelial cells. This sensitivity correlates with increased cellular proliferation rate and UPS stress rather than absolute proteasome levels. Proteasomal inhibition in vitro induces cell cycle arrest and the accumulation of p21 and p27 and triggers apoptosis via activation of caspase-3. Furthermore, treatment with the licensed proteasome inhibitor PS-341 slows the growth of ES-2 ovarian carcinoma xenograft in immunodeficient mice. In sum, elevated proliferation and metabolic rate resulting from malignant transformation of the epithelium stresses the UPS and renders ovarian carcinoma more sensitive to apoptosis in response to proteasomal inhibition. (Cancer Res 2006; 66(7): 3754-63)

BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells

“…42,43 This hypothesis remain to be confirmed, keeping in mind that, additional factors, other than BIM, BAX and BAK proteins, may account for GX15-070 to allow cell sensitization to bortezomib, such as the activation of the G 2 cell-cycle checkpoint by both agents. 26,44 In conclusion, the present study demonstrates that GX15-070 efficiently kills CLL cells and that high levels of BCL-2 phosphorylation at Ser70, due to MEK1/ERK pathway activation of CLL cells, reduce its activity and synergism with the proteasome inhibitor bortezomib. These results support the role of BCL-2 phosphorylation as a mechanism of resistance to BH3 mimetic compounds and suggest that combination approaches including ERK inhibitors, could enhance BH3 mimetic activity, both alone and in combination with proteasome inhibitors.…”

Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors

“…Carfilzomib, which has a greater affinity for proteasomes and lower off‐target toxicity, was licensed for treating patients with relapsed and/or refractory multiple myeloma in 2012. However, the efficacy of proteasome inhibitors in treating solid tumors, especially EOCs, has not been elucidated 47, 48, 49. Our findings offer clues to potential MuOC therapeutic targets by showing that PSMB8 inhibitors suppressed the growth of ovarian mucinous‐type cell lines in vitro .…”

HGF/c-Met pathway has a prominent role in mediating antiapoptotic signals through AKT in epithelial ovarian carcinoma

“…The tumor volume was measured as described earlier. 34 After 5 weeks treatment, mice were killed and individual tumors were weighted, then snap frozen in liquid nitrogen for storage. Table 1).…”