Discovery of novel small molecule inhibitors of S100P with in vitro anti-metastatic effects on pancreatic cancer cells

Camara, Ramatoulie; Ogbeni, Deborah; Gerstmann, Lisa; Ostovar, Mehrnoosh; Hurer, Ellie; Scott, M. Thompson; Mahmoud, Nasir G.; Radon, Tomasz P.; Crnogorac‐Jurčević, Tatjana; Patel, Pryank; Mackenzie, Louise; Chau, David; Kirton, Stewart B.; Rossiter, Sharon

doi:10.1016/j.ejmech.2020.112621

Cited by 25 publications

(19 citation statements)

References 33 publications

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“…S100A2/A10 have recently been suggested as negative prognostic biomarkers for pancreatic cancer ( Bachet et al, 2013 ; Bydoun et al, 2018a ). S100P/A11 are unfavorable to the prognosis of PAAD patients undergoing surgical resection ( Xiao et al, 2012 ; Camara et al, 2020 ). Collectively, the clinical significance of S100s members and their potential application in the development of PAAD have been highlighted, although their predictive potential and biological characteristics need to be further validated.…”

Section: Introductionmentioning

confidence: 99%

Prognostic Values and Clinical Significance of S100 Family Member’s Individualized mRNA Expression in Pancreatic Adenocarcinoma

Qiu

2021

Front. Genet.

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Objective: Pancreatic adenocarcinoma (PAAD) is a common malignant tumor worldwide. S100 family (S100s) is wildly involved in regulating the occurrence, development, invasion, metastasis, apoptosis, and drug resistance of many malignant tumors. However, the expression pattern, prognostic value, and oncological role of individual S100s members in PAAD need to be elucidated.Methods: The transcriptional expression levels of S100s were analyzed through the Oncomine and GEPIA, respectively. The protein levels of S100s members in PAAD were studied by Human Protein Atlas. The correlation between S100 mRNA expression and overall survival and tumor stage in PAAD patients was studied by GEPIA. The transcriptional expression correlation and gene mutation rate of S100s members in PAAD patients were explored by cBioPortal. The co-expression networks of S100s are identified using STRING and Gene MANIA to predict their potential functions. The correlation of S100s expression and tumor-infiltrating immune cells was tested by TIMER. Pathway activity and drug target analyzed by GSCALite.Results: 13 S100s members were upregulated in PAAD tissues. 15 S100s members were associated with TP53 mutation. Expression levels of S100A3/A5/A6/A10/A11/A14/A16/B/P/Z were significantly correlated with the pathological stage. Prognosis analysis demonstrated that PAAD patients with low mRNA levels of S100A1/B/Z or high levels of S100A2/A3/A5/A10/A11/A14/A16 had a poor prognosis. Immuno-infiltration analysis showed that the mRNA levels of S100A10/A11/A14/A16 were correlated with the infiltration degree of macrophages in PAAD. Drug sensitivity analysis showed that PAAD expressing high levels of S100A2/A6/A10/A11/A13/A14/A16 maybe resistant to small molecule drugs.Conclusion: This study identifies the clinical significance and biological functions of the S100s in PAAD, which may provide novel insights for the selection of prognostic biomarkers.

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Section: Introductionmentioning

confidence: 99%

Prognostic Values and Clinical Significance of S100 Family Member’s Individualized mRNA Expression in Pancreatic Adenocarcinoma

Qiu

2021

Front. Genet.

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“…Ramatoulie Camara et al used in silico methods to identify potential binding pockets in the NMR ensemble of S100P and successfully discovered several small molecule inhibitors that affect the S100P-RAGE interaction and S100P-mediated cell invasion, which can inhibit S100P-expressing PC cell invasion in vitro. This provides strong evidence of the potential of S100P inhibitors as chemotherapeutics for PC (159). In addition, through in vitro cell experiments and using mouse models, it has been found that cromolyn may bind to S100P to prevent activation of RAGE, thereby inhibiting S100P-mediated PC growth, survival and invasiveness (145).…”

Section: Othersmentioning

confidence: 86%

S100 Proteins in Pancreatic Cancer: Current Knowledge and Future Perspectives

Zhou

Guo

et al. 2021

Front. Oncol.

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Pancreatic cancer (PC) is a highly malignant tumor occurring in the digestive system. Currently, there is a lack of specific and effective interventions for PC; thus, further exploration regarding the pathogenesis of this malignancy is warranted. The S100 protein family, a collection of calcium-binding proteins expressed only in vertebrates, comprises 25 members with high sequence and structural similarity. Dysregulated expression of S100 proteins is a biomarker of cancer progression and prognosis. Functionally, these proteins are associated with the regulation of multiple cellular processes, including proliferation, apoptosis, growth, differentiation, enzyme activation, migration/invasion, Ca2+ homeostasis, and energy metabolism. This review highlights the significance of the S100 family in the diagnosis and prognosis of PC and its vital functions in tumor cell metastasis, invasion and proliferation. A further understanding of S100 proteins will provide potential therapeutic targets for preventing or treating PC.

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“…S100P, a calcium-binding protein, can advance tumor progression and metastasis in pancreatic and several other cancers ( 6 , 30 , 31 ). S100P has previously been demonstrated to regulate the proliferation, migratory and invasive capabilities of PAAD cells ( 6 ).…”

Section: Discussionmentioning

confidence: 99%

CircRNA circ_0092314 Induces Epithelial-Mesenchymal Transition of Pancreatic Cancer Cells via Elevating the Expression of S100P by Sponging miR-671

et al. 2021

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BackgroundCircular RNAs (circRNAs) is a novel class of non-coding RNAs that regulate gene expression during cancer progression. Circ_0092314 is a newly discovered circRNA that was upregulated in pancreatic cancer (PAAD) tissues. However, the detailed functions and underlying mechanisms of circ_0092314 in PAAD cells remain unclear.MethodsWe first determined the expression of circ_0092314 in PAAD and normal tissues and further investigated the functional roles of circ_0092314 in regulating epithelial-mesenchymal transition (EMT) of PAAD cells. We also assessed the regulatory action of circ_0092314 on the microRNA-671 (miR-671) and its target S100P.ResultsCirc_0092314 was markedly upregulated in PAAD tissues and cells, and its overexpression was closely correlated with worse prognosis of PAAD patients. Functionally, circ_0092314 promotes proliferation, invasion and EMT in vitro and tumor growth in vivo. Mechanistically, we demonstrated that circ_0092314 directly binds to miR-671 and relieve its suppression of the downstream target S100P, which induces EMT and activates the AKT signaling pathway. The tumor-promoting effects caused by overexpression of circ_0092314 could be revered by re-expression of miR-671 in PAAD cells.ConclusionsOverall, our study demonstrates that circ_0092314 exerts critical roles in promoting the EMT features of PAAD cells, and provides insight into how elevated expression of circ_0092314 might influence PAAD progression.

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Discovery of novel small molecule inhibitors of S100P with in vitro anti-metastatic effects on pancreatic cancer cells

Cited by 25 publications

References 33 publications

Prognostic Values and Clinical Significance of S100 Family Member’s Individualized mRNA Expression in Pancreatic Adenocarcinoma

Prognostic Values and Clinical Significance of S100 Family Member’s Individualized mRNA Expression in Pancreatic Adenocarcinoma

S100 Proteins in Pancreatic Cancer: Current Knowledge and Future Perspectives

CircRNA circ_0092314 Induces Epithelial-Mesenchymal Transition of Pancreatic Cancer Cells via Elevating the Expression of S100P by Sponging miR-671

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