Year : 2018 | Volume
: 7 | Issue : 1 | Page : 49--50
|How to cite this article:|
. Journal Scan.J Clin Sci Res 2018;7:49-50
|How to cite this URL:|
. Journal Scan. J Clin Sci Res [serial online] 2018 [cited 2020 Sep 21 ];7:49-50
Available from: http://www.jcsr.co.in/text.asp?2018/7/1/49/249625
Molecular signatures associated with treatment of triple-negative MDA-MB231 breast cancer cells with histone deacetylase inhibitors JAHA and SAHA
Jay Amin hydroxamic acid (JAHA; N8- ferrocenyl-N1-hydroxy-octanediamide) is a ferrocene-containing analogue of the histone deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA). JAHA's cytotoxic activity on MDA-MB231 triple-negative breast cancer (TNBC) cells at 72 h has been previously demonstrated with an IC50 of 8.45 μM. JAHA's lethal effect was found linked to perturbations of cell cycle, mitochondrial activity, signal transduction and autophagy mechanisms. To glean novel insights on how MDA-MB231 breast cancer cells respond to the cytotoxic effect induced by JAHA, and to compare the biological effect with the related compound SAHA, we have employed a combination of differential display – polymerase chain reaction (PCR), proteome analysis and COMET assay techniques – and shown some differences in the molecular signature profiles induced by exposure to either HDACis. In particular, in contrast to the more numerous and diversified changes induced by SAHA, JAHA has shown a more selective impact on expression of molecular signatures involved in antioxidant activity and DNA repair. Besides expanding the biological knowledge of the effect exerted by the modifications in compound structures on cell phenotype, the molecular elements put in evidence in our study may provide promising targets for therapeutic interventions on TNBCs.
Patients diagnosed with negative for oestrogen receptors, progesterone receptors and HER2 are called TNBC, and they are non-responders to hormonal therapies and to HER2-negative targeting drugs and usually associated with worse prognosis than other breast cancers. In this study, Librizzi et al., 2017 focussed on HDACis (JAHA) and compared with the biological effect of vorinostat or SAHA to show different molecular signature profiles induced by exposition using a combination of differential display – PCR, proteome analysis and COMET assay techniques. Authors have established molecular signatures as biomarkers involved in antioxidant activity and DNA repair in response to JAHA in HDACi in a TNBC cell model. Extension of the work may provide targets of TNBCs for the development of diagnostics and therapeutics.
Librizzi M, Caradonna F, Cruciata I, Dębski J, Sansook S, Dadlez M, et al. Molecular signatures associated with treatment of triple-negative MDA-MB231 breast cancer cells with histone deacetylase inhibitors JAHA and SAHA. Chem Res Toxicol 2017;30:2187-96.
Networks of enzymatically oxidized membrane lipids support calcium-dependent coagulation factor binding to maintain hemostasis
Blood coagulation functions as part of the innate immune system by preventing bacterial invasion, and it is critical to stop blood loss (haemostasis). Coagulation involves the external membrane surface of activated platelets and leucocytes. Using lipidomic, genetic, biochemical and mathematical modelling approaches, we found that enzymatically oxidised phospholipids (eoxPLs) generated by the activity of leucocyte or platelet lipoxygenases (LOXs) were required for normal haemostasis and promoted coagulation factor activities in a Ca2+- and phosphatidylserine-dependent manner. In wild-type mice, hydroxyeicosatetraenoic acid–phospholipids (HETE-PLs) enhanced coagulation and restored normal haemostasis in clotting-deficient animals genetically lacking p12-LOX or 12/15-LOX activity. Murine platelets generated 22 eoxPL species, all of which were missing in the absence of p12-LOX. Humans with the thrombotic disorder anti-phospholipid syndrome (APS) had statistically significantly increased HETE-PLs in platelets and leucocytes, as well as greater HETE-PL immunoreactivity, than healthy controls. HETE-PLs enhanced membrane binding of the serum protein b2-glycoprotein 1 (b2GP1), an event considered central to the autoimmune reactivity responsible for APS symptoms. Correlation network analysis of 47 platelet eoxPL species in platelets from APS and control subjects identified their enzymatic origin and revealed a complex network of regulation, with the abundance of 31 p12-LOX–derived eoxPL molecules substantially increased in APS. In summary, circulating blood cells generate networks of eoxPL molecules, including HETE-PLs, which change membrane properties to enhance blood coagulation and contribute to the excessive clotting and immunoreactivity of patients with APS.
APS is an acquired pro-thrombotic autoimmune disorder characterised by vascular thrombosis caused by a diverse family of circulating 'anti-phospholipid' antibodies. Lauder et al., 2017 revealed the pro-coagulant mechanisms of endogenously generated LOX-derived eoxPLs from platelets and leucocytes through biochemical, genetic, clinical, mathematical and lipidomic approaches. Amongst the 47 most abundant eoxPL species in platelets, 31 p12-LOX–derived eoxPL molecules bind with b2GP1 and promote coagulation which in turn chronically increased in human venous thrombotic disease associated with APS. These findings may have prime role in development of new diagnostics or therapeutics to control thrombotic diseases.
Lauder SN, Allen-Redpath K, Slatter DA, Aldrovandi M, O'Connor A, Farewell D, et al. Networks of enzymatically oxidized membrane lipids support calcium-dependent coagulation factor binding to maintain hemostasis. Sci Signal 2017;10. pii: eaan2787.
Large-scale proteomics identifies matrix metalloproteinase-7 as a sentinel of epithelial injury and of biliary atresia
Biliary atresia is a progressive infantile cholangiopathy of complex pathogenesis. Although early diagnosis and surgery are the best predictors of treatment response, current diagnostic approaches are imprecise and time-consuming. We used large-scale, quantitative serum proteomics at the time of diagnosis of biliary atresia and other cholestatic syndromes (serving as disease controls) to identify biomarkers of disease. In a discovery cohort of 70 subjects, the lead biomarker was matrix metalloproteinase-7 (MMP-7), which retained high distinguishing features for biliary atresia in two validation cohorts. Notably, the diagnostic performance reached 95% when MMP-7 was combined with g-glutamyl-transpeptidase (GGT), a marker of cholestasis. Using human tissue and an experimental model of biliary atresia, we found that MMP-7 is primarily expressed by cholangiocytes, released upon epithelial injury, and promotes the experimental disease phenotype. Thus, we propose that serum MMP-7 (alone or in combination with GGT) is a diagnostic biomarker for biliary atresia and may serve as a therapeutic target.
Lertudomphonwanit et al., 2017 reported MMP-7 as the best biomarkers for early diagnosis and to develop therapeutics for biliary atresia by means of serum proteomic analysis of humans and mice, gene expression and immunohistochemical analysis of MMP-7, GGT and ENCPP.
Lertudomphonwanit C, Mourya R, Fei L, Zhang Y, Gutta S, Yang L, et al. Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia. Sci Transl Med 2017;9. pii: eaan8462.
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Conflicts of interest
There are no conflicts of interest.
V. Suresh, A. R. Bitla
Provenanace and peer review commissioned; internally peer reviewed.