Specific microRNA–mRNA Regulatory Network of Colon Cancer Invasion Mediated by Tissue Kallikrein–Related Peptidase 6

Sells, Earlphia; Pandey, Ritu; Chen, Hwudaurw; Skovan, Bethany A.; Cui, Haiyan; Ignatenko, Natalia A.

doi:10.1016/j.neo.2017.02.003

Cited by 34 publications

(39 citation statements)

References 51 publications

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“…HCT116 colon cancer cells with knockdown of KLK6 expression (shKLK6 cells) were generated by stable transfection of SureSilencing shRNA plasmids (SureSilencing shRNAs, QIAGEN, Inc.), targeting the KLK6 gene using short-hairpin RNA (Fig. S2) [16]. Cell growth conditions are listed in the ESM.…”

Section: Methodsmentioning

confidence: 99%

Detection of Enzyme Activity and Inhibition during Studies in Solution, In Vitro and In Vivo with CatalyCEST MRI

et al. 2017

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Purpose The detection of enzyme activities and evaluation of enzyme inhibitors have been challenging with magnetic resonance imaging (MRI). To address this need, we have developed a diamagnetic, nonmetallic contrast agent and a protocol known as catalyCEST MRI that uses chemical exchange saturation transfer (CEST) to detect enzyme activity as well as enzyme inhibition. Procedures We synthesized a diamagnetic MRI contrast agent that has enzyme responsive and enzyme unresponsive CEST signals. We tested the ability of this agent to detect the activity of kallikrein 6 (KLK6) in biochemical solutions, in vitro and in vivo, with and without a KLK6 inhibitor. Results The agent detected KLK6 activity in solution and also detected KLK6 inhibition by antithrombin III. KLK6 activity was detected during in vitro studies with HCT116 colon cancer cells, relative to the detection of almost no activity in a KLK6-knockdown HCT116 cell line and HCT116 cells treated with antithrombin III inhibitor. Finally, strong enzyme activity was detected within an in vivo HCT116 tumor model, while lower enzyme activity was detected in a KLK6 knockdown tumor model and in the HCT116 tumor model treated with antithrombin III inhibitor. In all cases, comparisons of the enzyme responsive and enzyme unresponsive CEST signals were critical for the detection of enzyme activity. Conclusions This study has established that catalyCEST MRI with an exogenous diaCEST agent can evaluate enzyme activity and inhibition in solution, in vitro and in vivo.

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Section: Methodsmentioning

confidence: 99%

Detection of Enzyme Activity and Inhibition during Studies in Solution, In Vitro and In Vivo with CatalyCEST MRI

et al. 2017

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“…We have previously shown that knockdown of KLK6 reduces migration and invasion of HCT116 cells in vitro. [13] In order to test whether this effect could be recapitulated with small molecule KLK6 inhibitors, we measured the ability of 32 to reduce invasion of HCT116 cells. Because the enantiomer of 32 was never prepared, compound 9, the enantiomer of hit 5, was used as an inactive control substance.…”

Section: Lead Compound Pharmacokinetic Propertiesmentioning

confidence: 99%

“…[12] KLK6-promoted migration was also observed in colon cancer, where knockdown of KLK6 reduced migration and invasion of HCT116 cells in vitro. [13] Furthermore, in an orthotopic colon cancer mouse model, mice injected with KLK6 positive HCT116 cells had significantly more metastases and worse survival than mice injected with shKLK6 HCT116 clones. [13] Nevertheless, the role of KLK6 needs further investigation in these and other types of cancers, as its role is clearly tumordependent.…”

Section: Introductionmentioning

confidence: 99%

“…[13] Furthermore, in an orthotopic colon cancer mouse model, mice injected with KLK6 positive HCT116 cells had significantly more metastases and worse survival than mice injected with shKLK6 HCT116 clones. [13] Nevertheless, the role of KLK6 needs further investigation in these and other types of cancers, as its role is clearly tumordependent. In head-and-neck cancer for example, high levels of KLK6 have been associated with a better prognosis for the patients, resulting in reduced aggressiveness of the disease.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Structure–Activity Relationships of N-(4-Benzamidino)-Oxazolidinones–Potent and Selective Inhibitors of Kallikrein-Related Peptidase 6

Vita¹,

Smits²,

Hurk³

et al. 2019

Preprint

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Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins. Aberrant expression of KLK6 has been found in different cancers and neurodegenerative diseases, and KLK6 is currently studied as a potential target in these pathologies. We report a novel series of KLK6 inhibitors discovered in a high-throughput screen within the European Lead Factory program. Structure-guided design based on docking studies enabled rapid progression of a hit cluster to inhibitors with improved potency, selectivity and pharmacokinetic properties. In particular, inhibitors 32 and 34 have single digit nanomolar potency against KLK6, with over 25-fold and 100-fold selectivity, respectively, against the closely related enzyme trypsin. The most potent compound, 32, effectively reduces KLK6-dependent invasion of HCT116 cells. The high potency in combination with good solubility and low clearance of 32 make it a good chemical probe for KLK6 target validation in vitro and potentially in vivo.

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“…Probably, as Zheng et al 125 suggest, ING5 is up regulated at cytoplasmic level in colorectal cancer cases. MNS1 (meiosis specific nuclear structural 1) was found to be down regulated via knockdown of KLK6 127 . KLK6 is observed to be highly regulated in colorectal cancer cases and facilitates in the invasion-metastasis formation via specific downstream network of miRNA-mRNA effectors.…”

Section: Dicationmentioning

confidence: 99%

Revealing ETC-1922159 Affected Unknown 3rd order WNT10B-X-X Combinations, in Silico

Sinha¹

2017

Preprint

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WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. WNTs have been found to directly affect the stemness of the tumor cells via regulation of ASCL2. Switching off the ASCL2 literally blocks the stemness process of the tumor cells and vice versa. Furthermore, recent findings suggest BVES to be highly suppressed in malignancies and in vitro deletions of BVES show higher Wnt signaling activity to induce stemness. WNT10B was found to be highly expressed in such cases. Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. For example, WNT10B-ASCL2 is one such 2 nd order combination whose relation needs to be tested under the influence of recently developed porcupine-WNT inhibitor ETC-1922159. The inhibitor is known to suppress PORCN (porcupine) and thus inhibit a range of oncogenes known to be directly or indirectly affected by the Wnts. In a recent unpublished work in bioRxiv, Sinha 1 , we had the opportunity to rank these unknown biological hypotheses for down regulated genes at 2 nd order level after the drug was administered. The in silico observations showed that the combination of WNT10B-ASCL2 was assigned a relatively lower rank, thus validating the pipeline's efficacy with the confirmed wet lab experiment that indicate that both WNT10B and ASCL2 were down regulated after treatment in cancer cells. Here, we take one step further by in silico analysis of the 3 rd order combinations of WNT10B-X-X (X can be known or unknown factor), from a range of 100 randomly picked down regulated genes after ETC-1922159 treatment. The pipeline uses the density based HSIC (Hilbert Schmidt Information Criterion) sensitivity index with an rbf (radial basis function) kernel, which is known to be highly effective in sensitivity analysis. Various unknown/unexplored/untested 3 rd order biological hypotheses emerge some of which are confirmed in wet lab, while others need to be tested. The potential of such ranking is indispensable in the current era of search in a vast combinatorial forest. KEYWORDS -WNT pathway; porcupine inhibitor ETC-1922159; sensitivity analysis; colorectal cancer; unknown biological hypotheses; combinatorial search space; support vector ranking Conference, from 6-11 August 2017, held Significance WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. Often, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be involved in the pathway. The current work reveals at in silico level, the 3rd order WNT10B associated combinations that might be affected by the admin...

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Specific microRNA–mRNA Regulatory Network of Colon Cancer Invasion Mediated by Tissue Kallikrein–Related Peptidase 6

Cited by 34 publications

References 51 publications

Detection of Enzyme Activity and Inhibition during Studies in Solution, In Vitro and In Vivo with CatalyCEST MRI

Detection of Enzyme Activity and Inhibition during Studies in Solution, In Vitro and In Vivo with CatalyCEST MRI

Synthesis and Structure–Activity Relationships of N-(4-Benzamidino)-Oxazolidinones–Potent and Selective Inhibitors of Kallikrein-Related Peptidase 6

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

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