Abstract
BackgroundThe ubiquitin-proteasome system and macroautophagy (hereafter referred to autophagy) are two complementary pathways for protein degradation. Emerging evidence suggests that proteasome inhibition might be a promising approach for tumor therapy. Accumulating data suggest that autophagy is activated as a compensatory mechanism upon proteasome activity is impaired.MethodAutophagy activation was measured using acridine orange staining and LC3 transition. Cell viability and apoptosis were measured using MTT assay and flow cytometry, respectively. Beclin 1 expression vectors or shRNA against Beclin 1 (shBeclin 1) were transfected to investigate the role of Beclin 1 in autophagy activation and cytotoxicity of ovarian cancer cells induced by proteasome inhibitors.ResultsProteasome inhibitors suppressed proliferation and induced autophagy in ovarian cancer cells. Neither phosphoinositide 3-kinase (PI3K) inhibitors nor shRNA against Beclin 1 could abolish the formation of acidic vacuoles and the processing of LC3 induced by proteasome inhibitors. Moreover, Beclin 1 overexpression enhanced anti-proliferative effects of proteasome inhibitors in ovarian cancer cells.ConclusionsFor the first time, the current study demonstrated that proteasome inhibitors induced PI3K and Beclin 1-independent autophagy in ovarian cancer cells. In addition, this study revealed autophagy-independent tumor suppressive effects of Beclin 1 in ovarian cancer cells.
Highlights
The ubiquitin-proteasome system and macroautophagy are two complementary pathways for protein degradation
Neither phosphoinositide 3-kinase (PI3K) inhibitors nor Short hairpin RNA (shRNA) against Beclin 1 could abolish the formation of acidic vacuoles and the processing of LC3 induced by proteasome inhibitors
For the first time, the current study demonstrated that proteasome inhibitors induced PI3K and Beclin 1-independent autophagy in ovarian cancer cells
Summary
The ubiquitin-proteasome system and macroautophagy (hereafter referred to autophagy) are two complementary pathways for protein degradation. The ubiquitin-proteasome system serves as a major intracellular pathway for protein degradation in mammalian cells [1]. Many proteins involved in cancer cell growth and survival are regulated by proteasomal degradation [2]. In this connection, proteasome inhibitors constitute a novel class of anti-tumor agents with pre-clinical and clinical evidence of activity against hematologic malignancies and solid tumors [3]. Cell Viability (% of vehicle) * SKOV3 ** * * OVCAR3 * * **. 0 0.5 1 2 5 10 (μM) A2870 B A2870 vehicle.
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