Molecular Dynamics simulations of Inhibitor of Apoptosis Proteins and identification of potential small molecule inhibitors

Jayakumar, Jayanthi; Anishetty, Sharmila

doi:10.1016/j.bmcl.2014.03.046

Cited by 11 publications

(10 citation statements)

References 37 publications

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“…This prompted us to further investigate goblet cell like Muc2 expressing the cell line LS174T for linking between Survivin and ERS. Even thoughJayakumar et al has explored the molecular dynamics of Survivin recently in cancer cells [ 20 ], the expression dynamics was not described with regard to ERS induced by chemical agents such as TUN. The 6th hour time point, which was regarded as the highest expression of Survivin, along with Grp78 identified this as the end time point for all the experiments in our studies into the path of ERS-mediated apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Interplay between Endoplasmic Reticular Stress and Survivin in Colonic Epithelial Cells

Gundamaraju

Vemuri

Chong

et al. 2018

Cells

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Sustained endoplasmic reticular stress (ERS) is implicated in aggressive metastasis of cancer cells and increased tumor cell proliferation. Cancer cells activate the unfolded protein response (UPR), which aids in cellular survival and adaptation to harsh conditions. Inhibition of apoptosis, in contrast, is a mechanism adopted by cancer cells with the help of the inhibitor of an apoptosis (IAP) class of proteins such as Survivin to evade cell death and gain a proliferative advantage. In this study, we aimed to reveal the interrelation between ERS and Survivin. We initially verified the expression of Survivin in Winnie (a mouse model of chronic ERS) colon tissues by using immunohistochemistry (IHC) and immunofluorescence (IF) in comparison with wild type Blk6 mice. Additionally, we isolated the goblet cells and determined the expression of Survivin by IF and protein validation. Tunicamycin was utilized at a concentration of 10 µg/mL to induce ERS in the LS174T cell line and the gene expression of the ERS markers was measured. This was followed by determination of inflammatory cytokines. Inhibition of ERS was carried out by 4Phenyl Butyric acid (4PBA) at a concentration of 10 mM to assess whether there was a reciprocation effect. The downstream cell death assays including caspase 3/7, Annexin V, and poly(ADP-ribose) polymerase (PARP) cleavage were evaluated in the presence of ERS and absence of ERS, which was followed by a proliferative assay (EdU click) with and without ERS. Correspondingly, we inhibited Survivin by YM155 at a concentration of 100 nM and observed the succeeding ERS markers and inflammatory markers. We also verified the caspase 3/7 assay. Our results demonstrate that ERS inhibition not only significantly reduced the UPR genes (Grp78, ATF6, PERK and XBP1) along with Survivin but also downregulated the inflammatory markers such as IL8, IL4, and IL6, which suggests a positive correlation between ERS and the inhibition of apoptosis. Furthermore, we provided evidence that ERS inhibition promoted apoptosis in LS174T cells and shortened the proliferation rate. Moreover, Survivin inhibition by YM155 led to a comparable effect as that of ERS inhibition, which includes attenuation of ERS genes and inflammatory markers as well as the promotion of programmed cell death via the caspase 3/7 pathway. Together, our results propose the interrelation between ERS and inhibition of apoptosis assigning a molecular and therapeutic target for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Interplay between Endoplasmic Reticular Stress and Survivin in Colonic Epithelial Cells

Gundamaraju

Vemuri

Chong

et al. 2018

Cells

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“…Livin is the most recently identified member of the inhibitors of the apoptosis protein (IAP) family. Numerous evidence has demonstrated that Livin is associated with a high degree of malignancy and with poor prognosis in cancer patients (9)(10)(11). Livin inhibits cell apoptosis by binding to the regulators of apoptosis and promotes cell proliferation, migration and invasion (12).…”

Section: Introductionmentioning

confidence: 99%

Livin promotes the progression and metastasis of breast cancer through the regulation of epithelial‑mesenchymal transition via the p38/GSK3β pathway

et al. 2017

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Epithelial-mesenchymal transition (EMT) plays a pivotal role in the invasion and metastasis of breast cancer. Livin is a recently identified member of the inhibitors of the apoptosis protein family, which has been revealed to facilitate the progression of several types of cancer. However, the role of Livin in EMT and metastasis of breast cancer and its underlying mechanisms are not fully elucidated. In the present study, the levels of Livin mRNA and protein expression were found to be elevated in breast cancer tissues and cell lines. In addition, Livin expression was positively correlated with TNM stage and lymph node metastasis in total and triple-negative breast cancer (TNBC) cases. Livin overexpression enhanced the migratory and invasive abilities of the MCF-7 cells, accompanied by increases in vimentin, N-cadherin, Snail, MMP-2 and MMP-7 and a decrease in E-cadherin. Conversely, the downregulation of Livin had the opposite effect in MDA-MB-231 cells. Furthermore, the upregulation of Livin expression markedly stimulated the activation of the p38/GSK3β pathway, while the downregulation of Livin expression clearly suppressed the activation of the p38/GSK3β pathway. In conclusion, our results revealed that Livin induced EMT through the activation of the p38/GSK3β pathway, which in turn promoted the progression and metastasis of breast cancer, especially for TNBC.

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“…This indicated that the binding mode is intercalation, as reported in the literature [49]. The binding constants (Kb) were calculated for each of the ligands and their complexes by preceding as in Equation ( 1) [21], and the results are summarized in Table 9. Using data for the ligands and their uranyl complexes, it can be observed that with increasing DNA concentration, these compounds were hyperchromic.…”

Section: Dna-binding Studiesmentioning

confidence: 55%

“…This indicated that the binding mode is intercalation, as reported in the literature [49]. The binding constants (K b ) were calculated for each of the ligands and their complexes by preceding as in Equation ( 1) [21], and the results are summarized in Table 9. All of the complexes gave (K b ) values ranging from 1 × 10 −6 to 3.33 × 10 −5 .…”

Section: Dna-binding Studiesmentioning

confidence: 56%

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Synthesis, Structural Investigations, Molecular Docking, and Anticancer Activity of Some Novel Schiff Bases and Their Uranyl Complexes

et al. 2021

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Three novel 2-aminopyrazine Schiff bases derived from salicylaldehyde derivatives and their uranyl complexes were synthesized and characterized by elemental analysis, UV-vis, FTIR, molar conductance, and thermal gravimetric analysis (TGA). The proposed structures were optimized using density functional theory (DFT/B3LYP) and 6–311G ∗(d,p) basis sets. All uranyl complexes are soluble in DMSO and have low molar conductance, which indicates that all the complexes are nonelectrolytes. The DNA binding of those Schiff bases and their uranyl complexes was studied using UV-vis spectroscopy, and screening of their ability to bind to calf thymus DNA (CT-DNA) showed that the complexes interact with CT-DNA through an intercalation mode, for which the Kb values ranged from 1 × 106 to 3.33 × 105 M−1. The anticancer activities of the Schiff base ligands and their uranyl complexes against two ovarian (Ovcar-3) and melanoma cell lines (M14) were investigated, and the results indicated that uranyl complexes exhibit better results than the Schiff base ligands. Molecular docking identified the distance, energy account, type, and position of links contributing to the interactions between these complexes and two different cancer proteins (3W2S and 2OPZ).

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Molecular Dynamics simulations of Inhibitor of Apoptosis Proteins and identification of potential small molecule inhibitors

Cited by 11 publications

References 37 publications

Interplay between Endoplasmic Reticular Stress and Survivin in Colonic Epithelial Cells

Interplay between Endoplasmic Reticular Stress and Survivin in Colonic Epithelial Cells

Livin promotes the progression and metastasis of breast cancer through the regulation of epithelial‑mesenchymal transition via the p38/GSK3β pathway

Synthesis, Structural Investigations, Molecular Docking, and Anticancer Activity of Some Novel Schiff Bases and Their Uranyl Complexes

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