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Staphylococcal nuclease domain containing-1 (SND1) promotes migration and invasion via angiotensin II type 1 receptor (AT1R) and TGF? signaling.

ABSTRACT: Staphylococcal nuclease domain containing-1 (SND1) is overexpressed in human hepatocellular carcinoma (HCC) patients and promotes tumorigenesis by human HCC cells. We now document that SND1 increases angiotensin II type 1 receptor (AT1R) levels by increasing AT1R mRNA stability. This results in activation of ERK, Smad2 and subsequently the TGF? signaling pathway, promoting epithelial-mesenchymal transition (EMT) and migration and invasion by human HCC cells. A positive correlation was observed between SND1 and AT1R expression levels in human HCC patients. Small molecule inhibitors of SND1, alone or in combination with AT1R blockers, might be an effective therapeutic strategy for late-stage aggressive HCC.

SUBMITTER: Santhekadur PK

PROVIDER: S-EPMC4050181 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Staphylococcal nuclease domain containing-1 (SND1) promotes migration and invasion via angiotensin II type 1 receptor (AT1R) and TGFβ signaling.

Santhekadur Prasanna K PK Akiel Maaged M Emdad Luni L Gredler Rachel R Srivastava Jyoti J Rajasekaran Devaraja D Robertson Chadia L CL Mukhopadhyay Nitai D ND Fisher Paul B PB Sarkar Devanand D

FEBS open bio 20140401

Staphylococcal nuclease domain containing-1 (SND1) is overexpressed in human hepatocellular carcinoma (HCC) patients and promotes tumorigenesis by human HCC cells. We now document that SND1 increases angiotensin II type 1 receptor (AT1R) levels by increasing AT1R mRNA stability. This results in activation of ERK, Smad2 and subsequently the TGFβ signaling pathway, promoting epithelial-mesenchymal transition (EMT) and migration and invasion by human HCC cells. A positive correlation was observed b ...[more]

PMID: 24918049

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Project description:Metastatic breast cancer is a prime health concern and leading health burden across the globe. Previous efforts have shown that protein-protein interaction between Metadherin and Staphylococcal nuclease domaincontaining 1 (SND1) promotes initiation of breast cancer, progression, therapy resistance and metastasis. Therefore, small drug molecules that can interrupt the Metadherin and SND1 interaction may be ideal to suppress tumor growth, metastasis and increases chemotherapy sensitivity of triple negative breast cancer. Here, in this study, structure based virtual screening was conducted against the reported active site of SND1 enzyme, which revealed three promising lead molecules from Asinex library. These compounds were; BAS_00381028, BAS_00327287, and BAS_01293454 with binding energy score -10.25 kcal/mol, -9.65 kcal/mol and -9.32 kcal/mol, respectively. Compared to control (5-chloro-2-methoxy-N-([1,2,4]triazolo[1,5-a]pyridin-8-yl)benzene-1-sulfonamide) the lead molecules showed robust hydrophilic and hydrophobic interactions with the enzyme and revealed stable docked conformation in molecular dynamics simulation. During the simulation time, the compounds reported stable dynamics with no obvious fluctuation in binding mode and interactions noticed. The mean root mean square deviation (RMSD) of BAS_00381028, BAS_00327287, and BAS_01293454 complexes were 1.87 Å, 1.75 Å, 1.34 Å, respectively. Furthermore, the MM/GBSA analysis was conduction on the simulation trajectories of complexes that unveiled binding energy score of -19.25 kcal/mol, -27.03 kcal/mol, -34.6 kcal/mol and -29.61 kcal/mol for control, BAS_00381028, BAS_00327287, and BAS_01293454, respectively. In MM/PBSA, the binding energy value of for control, BAS_00381028, BAS_00327287, and BAS_01293454 was -20.45 kcal/mol, -27.89 kcal/mol, -36.41 kcal/mol and -32.01 kcal/mol, respectively. Additionally, the compounds were classified as druglike and have favorable pharmacokinetic properties. The compounds were predicted as promising leads and might be used in experimental investigation to study their anti-SND1 activity.

Dataset Information

Staphylococcal nuclease domain containing-1 (SND1) promotes migration and invasion via angiotensin II type 1 receptor (AT1R) and TGF? signaling.

Publications

Staphylococcal nuclease domain containing-1 (SND1) promotes migration and invasion via angiotensin II type 1 receptor (AT1R) and TGFβ signaling.

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