Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease

Prakash, Varsha; Carson, Brittany B.; Feenstra, Jennifer M.; Dass, Randall A.; Sekyrová, Petra; Hoshino, Ayuko; Petersen, Julian; Guo, Yuan; Parks, Matthew; Kurylo, Chad M.; Batchelder, Jake E.; Hallermalm, Kristian; Hashimoto, Ayako; Rundqivst, Helene; Condeelis, John S.; Allis, C. David; Drygin, Denis; Nieto, M. Ángela; Andäng, Michael; Percipalle, Piergiorgio; Bergh, Jonas; Adameyko, Igor; Farrants, Ann Kristin Östlund; Hartman, Johan; Lyden, David; Pietras, Kristian; Blanchard, Scott C.; Vincent, C. Theresa

doi:10.1038/s41467-019-10100-8

Cited by 174 publications

(192 citation statements)

References 79 publications

Supporting

Mentioning

173

Contrasting

Order By: Relevance

“…Moreover, we showed that the migratory capability of the PANC-1 cells was inhibited, but this could not be correlated with the expression of EMT markers. The lack of vimentin modulation is in line with the results of Prakash and collaborators in NNuMG cells treated with CX-5461 [14]. However, we found an upregulation of SNAIL1 mRNA expression after CX-5461 exposure in PDAC-3 and SUIT-2-28 cells, whereas the previous study [14] shows only an increase of SNAIL1 in transforming growth factor β (TGF-β) stimulated cells treated with CX-5461.…”

Section: Discussionsupporting

confidence: 91%

See 1 more Smart Citation

CX-5461 Inhibits Pancreatic Ductal Adenocarcinoma Cell Growth, Migration and Induces DNA Damage

et al. 2019

View full text Add to dashboard Cite

Background: Inhibition of ribosome biogenesis has recently emerged as a promising strategy for the treatment of metastatic tumors. The RNA polymerase I inhibitor CX-5461 has shown efficacy in a panel of cancer types and is currently being tested in clinical trials. However, further preclinical studies to unravel molecular mechanisms underlying the activity of this drug are warranted. Methods: In this study, we have investigated the effects of CX-5461 on cell growth and migration of pancreatic cancer cells by the sulforhodamine-B and wound healing assay, respectively. Furthermore, we assessed the expression of epithelial-to-mesenchymal transition (EMT) genes by qRT-PCR, while protein expression of DNA damage marker phospho-H2A.X was studied by Western blot and immunofluorescence. Results: CX-5461 inhibits pancreatic cancer cell growth in the nanomolar range and inhibits the migratory capability of the cells. Additionally, CX-5461 induced expression of EMT factor SNAI1 and caused DNA double-strand breaks as measured by increased expression of phospho-H2A.X. Conclusion: This study demonstrated that CX-5461 is active against pancreatic cancer cells and modulation of EMT factors, as well as increased expression of phospho-H2A.X, support further pre-/clinical investigations, including the analyses of these markers.

show abstract

Section: Discussionsupporting

confidence: 91%

“…The high sensitivity of the tested PC cells to CX-5461 and previous findings suggesting that ribosome biogenesis contributes to metastatic cancer progression [14] prompted us to investigate the effect of this drug on cell migration, using the wound healing assay.…”

Section: Cx-5461 Inhibits Pancreatic Cancer Cell Growth In Nanomolar mentioning

confidence: 99%

CX-5461 Inhibits Pancreatic Ductal Adenocarcinoma Cell Growth, Migration and Induces DNA Damage

et al. 2019

View full text Add to dashboard Cite

show abstract

“…A salient feature of spindle MBCs, which are highly proliferative and exhibit pathological evidence of EMT with elongated cancer cells, is upregulated expression of E2F and MYC pathway proteins, ribosomal proteins and transcriptional and translational processes. These findings are intriguing based on data showing that E2F and MYC are key drivers of cancer cell proliferation and EMT processes, where ribosome biogenesis and increased translation play an essential role 30,31 . These data also suggest that spindle MBC have a deregulated balance between translation and metabolic pathways, which needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Quantitative proteomic landscape of metaplastic breast carcinoma pathological subtypes and their relationship to triple-negative tumors

et al. 2020

View full text Add to dashboard Cite

Metaplastic breast carcinoma (MBC) is a highly aggressive form of triple-negative cancer (TNBC), defined by the presence of metaplastic components of spindle, squamous, or sarcomatoid histology. The protein profiles underpinning the pathological subtypes and metastatic behavior of MBC are unknown. Using multiplex quantitative tandem mass tag-based proteomics we quantify 5798 proteins in MBC, TNBC, and normal breast from 27 patients. Comparing MBC and TNBC protein profiles we show MBC-specific increases related to epithelial-to-mesenchymal transition and extracellular matrix, and reduced metabolic pathways. MBC subtypes exhibit distinct upregulated profiles, including translation and ribosomal events in spindle, inflammation-and apical junction-related proteins in squamous, and extracellular matrix proteins in sarcomatoid subtypes. Comparison of the proteomes of human spindle MBC with mouse spindle (CCN6 knockout) MBC tumors reveals a shared spindle-specific signature of 17 upregulated proteins involved in translation and 19 downregulated proteins with roles in cell metabolism. These data identify potential subtype specific MBC biomarkers and therapeutic targets.

show abstract

“…mTOR positively regulates several processes involved in ribosome biogenesis, including rRNA transcription as well as the synthesis of ribosomal proteins and components of ribosome assembly [67]. The mTORC2 component rictor is recruited to the nucleolar compartment during epithelial-to-mesenchymal transition (EMT)-associated ribosome biogenesis [68]. The role of rictor or mTORC2 in this compartment requires further investigation.…”

Section: Protein Synthesismentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

171

128

View full text Add to dashboard Cite

Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

show abstract

Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease

Cited by 174 publications

References 79 publications

CX-5461 Inhibits Pancreatic Ductal Adenocarcinoma Cell Growth, Migration and Induces DNA Damage

CX-5461 Inhibits Pancreatic Ductal Adenocarcinoma Cell Growth, Migration and Induces DNA Damage

Quantitative proteomic landscape of metaplastic breast carcinoma pathological subtypes and their relationship to triple-negative tumors

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Contact Info

Product

Resources

About