Potent antitumor agent proteasome inhibitors: a novel trigger for Bcl2 phosphorylation to induce apoptosis.

You, Sun-Ah; Basu, Aruna; Haldar, Subrata

doi:10.3892/ijo.15.4.625

Cited by 12 publications

(13 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent reports have demonstrated that drugs specifically blocking proteasome function are broadly active against 21,45 Our data strongly suggest that the combination of pro-caspase-3 overexpression with proteasome inhibitors can sensitise ovarian cancer cells to apoptosis. By using a suitable delivery system this approach could be applied for gene therapy of ovarian and other cancers.…”

Section: Discussionmentioning

confidence: 55%

Pro-caspase-3 overexpression sensitises ovarian cancer cells to proteasome inhibitors

et al. 2001

View full text Add to dashboard Cite

The ubiquitin-proteasome pathway plays a critical role in the degradation of several proteins involved in the cell cycle. Dysregulation of this pathway leads to inhibition of cellular proliferation and the induction of apoptosis. Ubiquitination and its downstream consequences have been investigated intensively as targets for the development of drugs for tumour therapy. Here we have investigated the mechanism of apoptosis induced by the proteasome inhibitors MG-132, lactacystin and calpain inhibitor I (ALLN), in the HEK 293 cell line and the ovarian cancer cell lines SKOV3 and OVCAR3. We have found strong caspase-3-like and caspase-6-like activation upon treatment of HEK 293 cells with MG-132. Using a tricistronic expression vector based on a tetracyclineresponsive system we generated stable SKOV3 nd OVCAR3 cell lines with inducible expression of pro-caspase-3. Induction of pro-caspase-3 expression in normally growing cells does not induce apoptosis. However, in the presence of the proteasome inhibitors MG-132, lactacystin or ALLN we found that cells overexpressing pro-caspase-3 are rapidly targeted for apoptosis. Our results demonstrate that procaspase-3 can sensitise ovarian cancer cells to proteasome inhibitor-induced apoptosis, and a combination of these approaches might be exploited for therapy of ovarian and other cancers.Cell Death and Differentiation (2001) 8, 256 ± 264.

show abstract

Section: Discussionmentioning

confidence: 55%

Pro-caspase-3 overexpression sensitises ovarian cancer cells to proteasome inhibitors

et al. 2001

View full text Add to dashboard Cite

show abstract

“…A similar effect, however, with the involvement of MCL-1 protein, can be mediated by active p38, another downstream substrate of IRE-1. Results of several reports showing that proteasome inhibition leads to the induction of the phosphorylation of anti-apoptotic proteins such as Bcl2, Bcl-xL or MCL-1, and autophagy [24,76,106,107] support the theory that both signal transduction pathways, i.e. JNK1/Bcl-2 and p38/MCL-1 become activated by proteasome inhibitors.…”

Section: Unfolded Protein Responsementioning

confidence: 60%

Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy

Wójcik

2014

Folia Histochem Cytobiol.

View full text Add to dashboard Cite

Abstract:The Ubiquitin-Proteasomes System (UPS) and autophagy, two main intracellular protein degradation pathways within the eukaryotic cells which were originally regarded as rather independent, seem to be very closely related. Proteasome inhibitors, including the multipathway inhibitor bortezomib, are drawing increased attention for their therapeutic potential in the treatment of chronic inflammation and cancer, especially tumours with a high degree of malignancy. The over-activation of autophagy induces cell death and may act as a powerful tumour-suppressing mechanism. However, autophagy, serving as an important mechanism to generate nutrients in time of cellular stresses, may directly contribute to the survival of cells treated with proteasome inhibitors, and in consequence, may decrease the effectiveness of therapy. Results of studies performed on several cancer cell lines demonstrated synergy between proteasome inhibitors and autophagy inhibitors. Those results became the base for ongoing clinical trials investigating autophagy inhibition in combination with anti-cancer therapies, including bortezomib. This review provides summary of the latest data on the functioning of the UPS and the mechanisms of autophagy. The new insights describing the main pathways of autophagy activation in response to UPS inhibition related to: (i) Unfolded Protein Response, (ii) PI3K/Akt/mTOR pathway, and (iii) formation of aggresomes, are discussed. It is concluded that concomitant inhibition of the two main cellular protein degradation systems may provide new therapeutic modalities for cancer treatment.

show abstract

“…In particular, the proteasome is the primary means by which oxidized, damaged, misfolded, and ubiquitinated proteins are degraded (Grune et al, 1997;Ullrich et al, 1999). Proteasome function is critical in maintaining cellular homeostasis, as evident by the ability of proteasome inhibitors to induce cell death in numerous cell types (Imajoh-Ohmi et al, 1995;Drexler, 1997;McDade et al, 1999;Orlowski, 1999;Wagenknecht et al, 1999;You et al, 1999), including neurons (Lopes et al, 1997;Boutillier et al, 1999;Keller et al, 1999). Recent studies indicate that proteasome activity is impaired in Alzheimer's disease brain (Keller et al, 2000), suggesting that proteasome inhibition may contribute to neuron death in neurodegenerative disorders.…”

mentioning

confidence: 99%

Proteasome inhibition results in increased poly-ADP-ribosylation: Implications for neuron death

Keller

Markesbery

2000

J. Neurosci. Res.

View full text Add to dashboard Cite

Potent antitumor agent proteasome inhibitors: a novel trigger for Bcl2 phosphorylation to induce apoptosis.

Cited by 12 publications

References 0 publications

Pro-caspase-3 overexpression sensitises ovarian cancer cells to proteasome inhibitors

Pro-caspase-3 overexpression sensitises ovarian cancer cells to proteasome inhibitors

Crosstalk between autophagy and proteasome protein degradation systems: possible implications for cancer therapy

Proteasome inhibition results in increased poly-ADP-ribosylation: Implications for neuron death

Contact Info

Product

Resources

About