Proteasome inhibition—a new target for brain tumours

Rashid, Fatima; Niklison-Chirou, Maria Victoria

doi:10.1038/s41420-019-0227-x

Cited by 11 publications

(8 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…reported that this system's inhibitors can be efficaciously used for the treatment of brain cancer. This report opened a new vision in this field [231]. Therefore, different ways for inhibiting this system in addition to ways to improve these inhibitors have been suggested up to now.…”

Section: Future Perspectivesmentioning

confidence: 99%

Ubiquitin–proteasome system and the role of its inhibitors in cancer therapy

et al. 2021

View full text Add to dashboard Cite

Despite all the other cells that have the potential to prevent cancer development and metastasis through tumour suppressor proteins, cancer cells can upregulate the ubiquitin–proteasome system (UPS) by which they can degrade tumour suppressor proteins and avoid apoptosis. This system plays an extensive role in cell regulation organized in two steps. Each step has an important role in controlling cancer. This demonstrates the importance of understanding UPS inhibitors and improving these inhibitors to foster a new hope in cancer therapy. UPS inhibitors, as less invasive chemotherapy drugs, are increasingly used to alleviate symptoms of various cancers in malignant states. Despite their success in reducing the development of cancer with the lowest side effects, thus far, an appropriate inhibitor that can effectively inactivate this system with the least drug resistance has not yet been fully investigated. A fundamental understanding of the system is necessary to fully elucidate its role in causing/controlling cancer. In this review, we first comprehensively investigate this system, and then each step containing ubiquitination and protein degradation as well as their inhibitors are discussed. Ultimately, its advantages and disadvantages and some perspectives for improving the efficiency of these inhibitors are discussed.

show abstract

Section: Future Perspectivesmentioning

confidence: 99%

Ubiquitin–proteasome system and the role of its inhibitors in cancer therapy

et al. 2021

View full text Add to dashboard Cite

show abstract

“…These hyperactive proteasome complexes support cancer cells by maintaining cell survival, cell cycle, and cell differentiation [60]. These findings accelerate continuing interest in expanding the application of proteasome inhibitors that have been successfully implemented for the treatment of hematological cancers [61][62][63]. However, the clinical efficacy of the first-in-class proteasome inhibitor, bortezomib, was limited in solid cancers [17].…”

Section: Discussionmentioning

confidence: 99%

Proteasome Complexes and Their Heterogeneity in Colorectal, Breast and Pancreatic Cancers

et al. 2021

View full text Add to dashboard Cite

Targeting the ubiquitin-proteasome system (UPS)-in particular, the proteasome complex-has emerged as an attractive novel cancer therapy. While several proteasome inhibitors have been successfully approved by the Food and Drug Administration for the treatment of hematological malignancies, the clinical efficacy of these inhibitors is unexpectedly lower in the treatment of solid tumors due to the functional and structural heterogeneity of proteasomes in solid tumors. There are ongoing trials to examine the effectiveness of compound and novel proteasome inhibitors that can target solid tumors either alone or in combination with conventional chemotherapeutic agents. The modest therapeutic efficacy of proteasome inhibitors such as bortezomib in solid malignancies demands further research to clarify the exact effects of these proteasome inhibitors on different proteasomes present in cancer cells. The structural, cellular localization and functional analysis of the proteasome complexes in solid tumors originated from different tissues provides new insights into the diversity of proteasomes' responses to inhibitors. In this study, we used an optimized iodixanol gradient ultracentrifugation to purify a native form of proteasome complexes with their intact associated protein partners enriched within distinct cellular compartments. It is therefore possible to isolate proteasome subcomplexes with far greater resolution than sucrose or glycerol fractionations. We have identified differences in the catalytic activities, subcellular distribution, and inhibitor sensitivity of cytoplasmic proteasomes isolated from human colon, breast, and pancreatic cancer cell lines. Our developed techniques and generated results will serve as a valuable guideline for investigators developing a new generation of proteasome inhibitors as an effective targeted therapy for solid tumors.

show abstract

“…BTZ specifically binds to 20S catalytic core of 26S proteasome to block UPP, engendering PTD stress [29]. The impairment of NF-κB, the stabilization of p53, pro-apoptotic proteins or BH3-only proteins, the depletion of ubiquitin, the increase of ER stress, or JNK pathway action due to PTD stress are all possible reasons for BTZ-induced apoptosis [30,31]. There are studies to claim BTZinduced apoptosis through p53-dependent pathway [32,33] or p53-independent pathway [34,35].…”

Section: The Function Of P53 In Sdd-or Ptd-induced Apoptosismentioning

confidence: 99%

Severe cellular stress drives apoptosis through a dual control mechanism independently of p53

Wang

Hung

et al. 2022

Cell Death Discov.

View full text Add to dashboard Cite

For past two decades, p53 has been claimed as the primary sensor initiating apoptosis. Under severe cellular stress, p53 transcriptional activity activates BH3-only proteins such as Bim, Puma, or Noxa to nullify the inhibitory effects of anti-apoptotic proteins on pro-apoptotic proteins for mitochondrial outer membrane permeabilization. Cellular stress determines the expression level of p53, and the amount of p53 corresponds to the magnitude of apoptosis. However, our studies indicated that Bim and Puma are not the target genes of p53 in three cancer models, prostate cancer, glioblastoma, and osteosarcoma. Bim counteracted with Bcl-xl to activate apoptosis independently of p53 in response to doxorubicin-induced severe DNA damage in prostate cancer. Moreover, the transcriptional activity of p53 was more related to cell cycle arrest other than apoptosis for responding to DNA damage stress generated by doxorubicin in prostate cancer and glioblastoma. A proteasome inhibitor that causes protein turnover dysfunction, bortezomib, produced apoptosis in a p53-independent manner in glioblastoma and osteosarcoma. p53 in terms of both protein level and nuclear localization in combining doxorubicin with bortezomib treatment was obviously lower than when using DOX alone, inversely correlated with the magnitude of apoptosis in glioblastoma. Using a BH3-mimetic, ABT-263, to treat doxorubicin-sensitive p53-wild type and doxorubicin-resistant p53-null osteosarcoma cells demonstrated only limited apoptotic response. The combination of doxorubicin or bortezomib with ABT-263 generated a synergistic outcome of apoptosis in both p53-wild type and p53-null osteosarcoma cells. Together, this suggested that p53 might have no role in doxorubicin-induced apoptosis in prostate cancer, glioblastoma and osteosarcoma. The effects of ABT-263 in single and combination treatment of osteosarcoma or prostate cancer indicated a dual control to regulate apoptosis in response to severe cellular stress. Whether our findings only apply in these three types of cancers or extend to other cancer types remains to be explored.

show abstract

Proteasome inhibition—a new target for brain tumours

Cited by 11 publications

References 24 publications

Ubiquitin–proteasome system and the role of its inhibitors in cancer therapy

Ubiquitin–proteasome system and the role of its inhibitors in cancer therapy

Proteasome Complexes and Their Heterogeneity in Colorectal, Breast and Pancreatic Cancers

Severe cellular stress drives apoptosis through a dual control mechanism independently of p53

Contact Info

Product

Resources

About