Proteases and Their Modulators in Cancer Therapy: Challenges and Opportunities

Song, Rao; Qiao, Wenliang; He, Jiang; Huang, Jiasheng; Luo, Youfu

doi:10.1021/acs.jmedchem.0c01640

Cited by 22 publications

(21 citation statements)

References 168 publications

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“…targeting all kinases; 54 - 57 ). The potential for proteases as synthetic lethal partners of PI3K inhibition has been neglected so far, although proteases are involved in all steps of cancer progression 26 , 58 . Therefore, we report here the application of degradome-wide inducible miR-E-libraries in cancer settings in combination with PI3K inhibition.…”

Section: Discussionmentioning

confidence: 99%

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RNA interference screens discover proteases as synthetic lethal partners of PI3K inhibition in breast cancer cells

Hölzen¹,

Mitschke²,

Schönichen³

et al. 2022

Theranostics

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Rationale: PI3K/mTOR signaling is frequently upregulated in breast cancer making inhibitors of this pathway highly promising anticancer drugs. However, PI3K-inhibitors have a low therapeutic index. Therefore, finding novel combinatory treatment options represents an important step towards clinical implementation of PI3K pathway inhibition in breast cancer therapy. Here, we propose proteases as potential synergistic partners with simultaneous PI3K inhibition in breast cancer cells. Methods: We performed mRNA expression studies and unbiased functional genetic synthetic lethality screens by a miR-E based knockdown system targeting all genome-encoded proteases, i.e. the degradome of breast cancer cells. Importantly theses RNA interference screens were done in combination with two PI3K pathway inhibitors. Protease hits were validated in human and murine breast cancer cell lines as well as in non-cancerous cells by viability and growth assays. Results: The degradome-wide genetic screens identified 181 proteases that influenced susceptibility of murine breast cancer cells to low dose PI3K inhibition. Employing independently generated inducible knockdown cell lines we validated 12 protease hits in breast cancer cells. In line with the known tumor promoting function of these proteases we demonstrated Usp7 and Metap2 to be important for murine and human breast cancer cell growth and discovered a role for Metap1 in this context. Most importantly, we demonstrated that Usp7, Metap1 or Metap2 knockdown combined with simultaneous PI3K inhibition resulted in synergistic impairment of murine and human breast cancer cell growth Conclusion: We successfully established proteases as combinatory targets with PI3K inhibition in human and murine breast cancer cells. Usp7, Metap1 and Metap2 are synthetic lethal partners of simultaneous protease/PI3K inhibition, which may refine future breast cancer therapy.

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Section: Discussionmentioning

confidence: 99%

“…In the present study, we set out to explore proteases as a fairly neglected class of enzymes in connection to PI3K signaling. Proteases often promote cancer progression and metastasis due to their connection to many signaling pathways 26 . In this respect a regulatory crosstalk of proteases and kinases has been postulated 27 .…”

Section: Introductionmentioning

confidence: 99%

RNA interference screens discover proteases as synthetic lethal partners of PI3K inhibition in breast cancer cells

Hölzen¹,

Mitschke²,

Schönichen³

et al. 2022

Theranostics

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show abstract

“…The complete multiple genome sequencing has enabled us to identify the different classes of proteases, but there are still many gaps in understanding the role of many proteases [254]. Some significant challenges are addressed by the protease group in the development and usage of technologies at GNF in understanding protease biology to develop protease-based targeted therapeutics [255].…”

Section: Current Challenges and Future Perspectivementioning

confidence: 99%

Fungal Proteases as Emerging Biocatalysts to Meet the Current Challenges and Recent Developments in Biomedical Therapies: An Updated Review

Naeem

Manzoor²,

Abid

et al. 2022

JoF

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With the increasing world population, demand for industrialization has also increased to fulfill humans’ living standards. Fungi are considered a source of essential constituents to produce the biocatalytic enzymes, including amylases, proteases, lipases, and cellulases that contain broad-spectrum industrial and emerging applications. The present review discussed the origin, nature, mechanism of action, emerging aspects of genetic engineering for designing novel proteases, genome editing of fungal strains through CRISPR technology, present challenges and future recommendations of fungal proteases. The emerging evidence revealed that fungal proteases show a protective role to many environmental exposures and discovered that an imbalance of protease inhibitors and proteases in the epithelial barriers leads to the protection of chronic eosinophilic airway inflammation. Moreover, mitoproteases recently were found to execute intense proteolytic processes that are crucial for mitochondrial integrity and homeostasis function, including mitochondrial biogenesis, protein synthesis, and apoptosis. The emerging evidence revealed that CRISPR/Cas9 technology had been successfully developed in various filamentous fungi and higher fungi for editing of specific genes. In addition to medical importance, fungal proteases are extensively used in different industries such as foods to prepare butter, fruits, juices, and cheese, and to increase their shelf life. It is concluded that hydrolysis of proteins in industries is one of the most significant applications of fungal enzymes that led to massive usage of proteomics.

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“…The cell proteostasis machinery consists of several major parts aimed at monitoring incorrectly assembled polypeptides and their complexes and includes molecular chaperones, autophagy, and the ubiquitin–proteasomal system of degradation (UPS) [ 7 ], which are functionally linked to each other [ 8 ]. Proteostasis is the process of regulating intracellular proteins to maintain the balance of the cell proteome, which is crucial for cancer cell survival [ 9 ]. Therapy targeted at the proteostasis system can be an effective way to enhance the sensitivity of cancer cells to antitumor therapy.…”

Section: Introductionmentioning

confidence: 99%

Combined Cytotoxic Effect of Inhibitors of Proteostasis on Human Colon Cancer Cells

et al. 2022

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Despite significant progress in the diagnosis and treatment of colorectal cancer, drug resistance continues to be a major limitation of therapy. In this regard, studies aimed at creating combination therapy are gaining popularity. One of the most promising adjuvants are inhibitors of the proteostasis system, chaperone machinery, and autophagy. The main HSP regulator, HSF1, is overactivated in cancer cells and autophagy sustains the survival of malignant cells. In this work, we focused on the selection of combination therapy for the treatment of rectal cancer cells obtained from patients after tumor biopsy without prior treatment. We characterized the migration, proliferation, and chaperone status in the resulting lines and also found them to be resistant to a number of drugs widely used in the clinic. However, these cells were sensitive to the autophagy inhibitor, chloroquine. For combination therapy, we used an HSF1 activity inhibitor discovered earlier in our laboratory, the cardenolide CL-43, which has already been proven as an auxiliary component of combined therapy in established cell lines. CL-43 effectively suppressed HSF1 activity and Hsp70 expression in all investigated cells. We tested the autophagy inhibitor, chloroquine, in combination with CL-43. Our results indicate that the use of an inhibitor of HSF1 activity in combination with an autophagy inhibitor results in effective cancer cell death, therefore, this therapeutic approach may be a promising treatment regimen for certain patients.

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Proteases and Their Modulators in Cancer Therapy: Challenges and Opportunities

Cited by 22 publications

References 168 publications

RNA interference screens discover proteases as synthetic lethal partners of PI3K inhibition in breast cancer cells

RNA interference screens discover proteases as synthetic lethal partners of PI3K inhibition in breast cancer cells

Fungal Proteases as Emerging Biocatalysts to Meet the Current Challenges and Recent Developments in Biomedical Therapies: An Updated Review

Combined Cytotoxic Effect of Inhibitors of Proteostasis on Human Colon Cancer Cells

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