The molecular function of kallikrein‐related peptidase 14 demonstrates a key modulatory role in advanced prostate cancer

Kryza, Thomas; Bock, Nathalie; Lovell, S.; Rockstroh, Anja; Lehman, Melanie; Lesner, Adam; Panchadsaram, Janaththani; Silva, Lakmali Munasinghage; Srinivasan, Srilakshmi; Snell, Cameron; Williams, Elizabeth D.; Fazli, Ladan; Gleave, Martin; Batra, Jyotsna; Nelson, Colleen C.; Tate, Edward W.; Harris, Jonathan M.; Hooper, John D.; Clements, Judith A.

doi:10.1002/1878-0261.12587

Cited by 15 publications

(34 citation statements)

References 62 publications

(72 reference statements)

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“…These results suggest that KLK8 may play different roles in different cancers, and the aberrant expression of KLK8 may serve as a potential clinical biomarker for cancer diagnosis or prognosis. KLK family members have been implicated in the pathogenesis and progression of malignant tumor [30,31]. For example, overexpression of KLK7 is found to stimulate colon cancer cell proliferation both in vivo and in vitro [32].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

Hua

Liu

et al. 2020

Preprint

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Background: Pancreatic ductal adenocarcinoma (PDAC) is a growing cause of cancer-related mortality worldwide. Kallikrein-related peptidase 8 (KLK8) has potential clinical values in many cancers. However, the clinicopathological significances of KLK8 in PDAC remain unknown. Methods: The relationship of KLK8 to clinicopathological features of PDAC was investigated based on public databases. KLK8 expression was examined in human PDAC tissues. Cell proliferation and apoptosis were evaluated in KLK8-overexpressed human pancreatic cancer cell lines Mia-paca-2 and Panc-1. The related signaling pathways of KLK8 involved in pancreatic cancer progression were analyzed by gene set enrichment analysis (GSEA) and further verified in in vitro studies. Results: KLK8 was up-regulated in tumor tissues in the TCGA-PAAD cohort, and was an independent prognostic factor for both overall survival and disease-free survival of PDAC. KLK8 mRNA and protein expressions were increased in PDAC tissues compared with para-cancerous pancreas. KLK8 overexpression exerted pro-proliferation and anti-apoptotic functions in Mia-paca-2 and Panc-1 cells. GSEA analysis showed that KLK8 was positively associated with PI3K-Akt-mTOR and Notch pathways. KLK8-induced pro-proliferation and anti-apoptotic effects in Mia-paca-2 and Panc-1 cells were attenuated by inhibitors for PI3K, Akt, and mTOR, but not by inhibitor for Notch.Conclusion: KLK8 overexpression exerts pro-proliferation and anti-apoptotic functions in pancreatic cancer cells via PI3K/Akt/mTOR pathway. Upregulated KLK8 in PDAC predicts poor prognosis and may be a potential therapeutic target for PDAC.

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Section: Discussionmentioning

confidence: 99%

Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

Hua

Liu

et al. 2020

Preprint

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“…Compounds 20, 31 and 39 were incubated with CM obtained from LNCaP-K14 cells, in which KLK14 expression has been placed under the control of a doxycycline-inducible promoter, stimulated with 10 nM DHT and 200 nM doxycycline (dox). 15 Streptavidin blotting revealed a single target between 25-32 KDa for each compound, labeled in a concentration-dependent manner (Fig. 4A), showing that the only detectable targets of these probes are their cognate proteases to the exclusion of other off-targets, emphasizing their impressive selectivity.…”

Section: Development Of Selective Inhibitors and Activity-based Probes For Klk2 And Klk14mentioning

confidence: 98%

“…1A), treatment with AR-targeted drugs may increase KLK14 expression to promote PCa cell migration and bone matrix colonization. 14,15 Despite recent progress in determining the pathophysiological roles of individual KLKs in PCa, the potential of KLK inhibitors for therapeutic intervention remains to be determined. Once secreted by PCa cells, KLKs do not work in isolation but as components of a complex network called the KLK activome (Fig.…”

Section: Introductionmentioning

confidence: 99%

A suite of activity-based probes to dissect the KLK activome in drug-resistant prostate cancer

Lovell

Zhang

Kryza

et al. 2021

Preprint

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Kallikrein-related peptidases (KLKs) are a family of secreted serine proteases, which form a network, the KLK activome, with an important role in proteolysis and signaling. In prostate cancer (PCa), increased KLK activity promotes tumor growth and metastasis through multiple biochemical pathways, and specific quantification and tracking of changes in the KLK activome could contribute to validation of KLKs as potential drug targets. Herein we report a technology platform based on novel activity-based probes (ABPs) and inhibitors with unprecedented potency and selectivity enabling simultaneous orthogonal analysis of KLK2, KLK3 and KLK14 activity in hormone-responsive PCa cell lines and tumor homogenates. Using selective inhibitors and multiplexed fluorescent activity-based protein profiling (ABPP) we dissect the KLK activome in PCa cells and show that increased KLK14 activity leads to a migratory phenotype. Furthermore, using biotinylated ABPs we show that active KLK molecules are secreted into the bone microenvironment by PCa cells following stimulation by osteoblasts suggesting KLK-mediated signaling mechanisms could contribute to PCa metastasis to bone. Together our findings show that ABPP is a powerful approach to dissect dysregulation of the KLK activome as a promising and previously underappreciated therapeutic target in advanced PCa.

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“…KLK-14 is another protease that is involved in prostate cancer progression, and its expression is elevated in metastatic and castration-resistant prostate cancer cells [70]. In pancreatic cancer, high KLK-7 expression is correlated with a poor prognosis [71], and silencing KLK-7 or the suppression of its activity with a small molecule inhibitor resulted in suppression of the proliferation, migration, and invasion of PANC-1 cells [72].…”

Section: Tumor-associated Trypsinogen (Tat) and Kallikrein-related Pementioning

confidence: 99%

The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators That Inhibit Their Activity

Park

Mahendiran

Richardson

2020

IJMS

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The role of extracellular proteases in cancer progression is well-known, especially in relation to the promotion of cell invasion through extracellular matrix remodeling. This also occurs by the ability of extracellular proteases to induce the shedding of transmembrane proteins at the plasma membrane surface or within extracellular vesicles. This process results in the regulation of key signaling pathways by the modulation of kinases, e.g., the epidermal growth factor receptor (EGFR). Considering their regulatory roles in cancer, therapeutics targeting various extracellular proteases have been discovered. These include the metal-binding agents di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), which increase c-MET degradation by multiple mechanisms. Both the direct and indirect inhibition of protease expression and activity can be achieved through metal ion depletion. Considering direct mechanisms, chelators can bind zinc(II) that plays a catalytic role in enzyme activity. In terms of indirect mechanisms, Dp44mT and DpC potently suppress the expression of the kallikrein-related peptidase—a prostate-specific antigen—in prostate cancer cells. The mechanism of this activity involves promotion of the degradation of the androgen receptor. Additional suppressive mechanisms of Dp44mT and DpC on matrix metalloproteases (MMPs) relate to their ability to up-regulate the metastasis suppressors N-myc downstream regulated gene-1 (NDRG1) and NDRG2, which down-regulate MMPs that are crucial for cancer cell invasion.

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The molecular function of kallikrein‐related peptidase 14 demonstrates a key modulatory role in advanced prostate cancer

Cited by 15 publications

References 62 publications

Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

A suite of activity-based probes to dissect the KLK activome in drug-resistant prostate cancer

The Role of Extracellular Proteases in Tumor Progression and the Development of Innovative Metal Ion Chelators That Inhibit Their Activity

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