Virtual screening-driven repositioning of etoposide as CD44 antagonist in breast cancer cells

Aguirre-Alvarado, Charmina; Segura‐Cabrera, Aldo; Velázquez-Quesada, Inés; Hernandez-Esquivel, Miguel A.; García-Pérez, Carlos A.; Guerrero-Rodriguez, Sandra; Ruiz-Moreno, Angel J.; Rodríguez-Moreno, Andrea; Pérez‐Tapia, Sonia Mayra; Velasco-Velázquez, Marco A.

doi:10.18632/oncotarget.8180

Cited by 19 publications

(13 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results indicate that CD44s-mediated Akt activation requires Akt downstream targets HAS2/HA. In support of this finding, addition of CD44 antibodies that block HA–CD44 interaction (30–33) resulted in inhibition of Akt activation, a phenotype that was observed in four different cell lines (Fig. 5D and E, Supplementary Fig.…”

Section: Resultssupporting

confidence: 70%

Akt Signaling Is Sustained by a CD44 Splice Isoform–Mediated Positive Feedback Loop

Liu

Cheng

2017

Cancer Research

View full text Add to dashboard Cite

Tumor cells nearly invariably evolve sustained PI3K/Akt signaling as an effective means to circumvent apoptosis and maintain survival. However, for those tumor cells that do not acquire PI3K/Akt mutations to achieve this end, the underlying mechanisms have remained obscure. Here, we describe the discovery of a splice isoform–dependent positive feedback loop that is essential to sustain PI3K/Akt signaling in breast cancer. Splice isoform CD44s promoted expression of the hyaluronan synthase HAS2 by activating the Akt signaling cascade. The HAS2 product hyaluronan further stimulated CD44s-mediated Akt signaling, creating a feed-forward signaling circuit that promoted tumor cell survival. Mechanistically, we identified FOXO1 as a bona fide transcriptional repressor of HAS2. Akt-mediated phosphorylation of FOXO1 relieved its suppression of HAS2 transcription, with FOXO1 phosphorylation status maintained by operation of the positive feedback loop. In clinical specimens of breast cancer, we established that the expression of CD44s and HAS2 was positively correlated. Our results establish a positive feedback mechanism that sustains PI3K/Akt signaling in tumor cells, further illuminating the nearly universal role of this pathway in cancer cell survival.

show abstract

Section: Resultssupporting

confidence: 70%

Akt Signaling Is Sustained by a CD44 Splice Isoform–Mediated Positive Feedback Loop

Liu

Cheng

2017

Cancer Research

View full text Add to dashboard Cite

show abstract

“…Moreover, therapies that destabilize neutrophil extracellular traps such as deoxyribonuclease (DNAase) administration might limit the propagation of thrombi resulting from superficial erosion 71 . Receptors such as CD44 expressed by neutrophils may bind hyaluronan and glycosaminoglycan enriched in plaques complicated by erosion, and furnish a potential therapeutic target 72 .…”

Section: Plaque Erosionmentioning

confidence: 99%

Acute Coronary Syndromes

2017

View full text Add to dashboard Cite

Well into the 21st century, we still triage acute myocardial infarction based on the presence or absence of ST segment elevation, a century-old technology. Meanwhile, we have learned a great deal regarding the pathophysiology and mechanisms of acute coronary syndromes (ACS) at clinical, pathological, cellular, and molecular levels. Contemporary imaging studies have shed new light into the mechanisms of ACS. This review discusses these advances and their implications for clinical management of the ACS for the future. Plaque rupture has dominated our thinking about ACS pathophysiology for decades. Yet, current evidence suggests that a sole focus on plaque rupture vastly oversimplifies this complex collection of diseases, and obscures other mechanisms that may mandate different management strategies. We propose to segment coronary artery thrombosis due to plaque rupture into cases with or without signs of concomitant inflammation. This distinction may have substantial therapeutic implications as direct anti-inflammatory interventions for atherosclerosis emerge. Coronary artery thrombosis due to plaque erosion may be on the rise in an era of intense lipid lowering. Identification of patients with of ACS due to erosion may permit a less invasive approach to management than the current standard of care. We also now recognize ACS that occur without apparent epicardial coronary artery thrombus or stenosis. Such events may arise from spasm, microvascular disease, or other pathways. Emerging management strategies may likewise apply selectively to this category of ACS. We advocate this more mechanistic approach to the categorization of ACS to provide a framework for future tailoring, triage, and therapy for patients in a more personalized and precise manner.

show abstract

“…MD simulation is a computational method for studying the physical movements of atoms and molecules, which are allowed to interact for a fixed period of time, giving a dynamical evolution of the system [11–14]. It is very useful in exploring enzyme-substrate interactions [15].…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulation reveals how phosphorylation of tyrosine 26 of phosphoglycerate mutase 1 upregulates glycolysis and promotes tumor growth

et al. 2017

View full text Add to dashboard Cite

Phosphoglycerate mutase 1 (PGAM1) catalyzes the eighth step of glycolysis and is often found upregulated in cancer cells. To test the hypothesis that the phosphorylation of tyrosine 26 residue of PGAM1 greatly enhances its activity, we performed both conventional and steered molecular dynamics simulations on the binding and unbinding of PGAM1 to its substrates, with tyrosine 26 either phosphorylated or not. We analyzed the simulated data in terms of structural stability, hydrogen bond formation, binding free energy, etc. We found that tyrosine 26 phosphorylation enhances the binding of PGAM1 to its substrates through generating electrostatic environment and structural features that are advantageous to the binding. Our results may provide valuable insights into computer-aided design of drugs that specifically target cancer cells with PGAM1 tyrosine 26 phosphorylated.

show abstract

Virtual screening-driven repositioning of etoposide as CD44 antagonist in breast cancer cells

Cited by 19 publications

References 68 publications

Akt Signaling Is Sustained by a CD44 Splice Isoform–Mediated Positive Feedback Loop

Akt Signaling Is Sustained by a CD44 Splice Isoform–Mediated Positive Feedback Loop

Acute Coronary Syndromes

Molecular dynamics simulation reveals how phosphorylation of tyrosine 26 of phosphoglycerate mutase 1 upregulates glycolysis and promotes tumor growth

Contact Info

Product

Resources

About