The interaction of p130Cas with <scp>PKN</scp>3 promotes malignant growth

Gemperle, Jakub; Dibus, Michal; Koudelková, Lenka; Rösel, Daniel; Brábek, Jan

doi:10.1002/1878-0261.12401

Cited by 16 publications

(15 citation statements)

References 61 publications

(148 reference statements)

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“…2 E; Supplementary Figure S5 B). Despite this fact and the decrease in FAK activity, MLN-treated PC3 cells showed a significant stimulation of AKT(S473, T308) kinase and prometastatic PRK3/PKN3(T718) [ 26 , 27 ] (Fig. 2 C; Supplementary Figure S5 A).…”

Section: Resultsmentioning

confidence: 99%

Mechanical stress shapes the cancer cell response to neddylation inhibition

Mittler

Obeïd

Haguet

et al. 2022

J Exp Clin Cancer Res

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Background The inhibition of neddylation by the preclinical drug MLN4924 represents a new strategy to combat cancer. However, despite being effective against hematologic malignancies, its success in solid tumors, where cell–cell and cell-ECM interactions play essential roles, remains elusive. Methods Here, we studied the effects of MLN4924 on cell growth, migration and invasion in cultured prostate cancer cells and in disease-relevant prostate tumoroids. Using focused protein profiling, drug and RNAi screening, we analyzed cellular pathways activated by neddylation inhibition. Results We show that mechanical stress induced by MLN4924 in prostate cancer cells significantly affects the therapeutic outcome. The latter depends on the cell type and involves distinct Rho isoforms. In LNCaP and VCaP cells, the stimulation of RhoA and RhoB by MLN4924 markedly upregulates the level of tight junction proteins at cell–cell contacts, which augments the mechanical strain induced by Rho signaling. This “tight junction stress response” (TJSR) causes the collapse of cell monolayers and a characteristic rupture of cancer spheroids. Notably, TJSR is a major cause of drug-induced apoptosis in these cells. On the other hand, in PC3 cells that underwent partial epithelial-to-mesenchymal transition (EMT), the stimulation of RhoC induces an adverse effect by promoting amoeboid cell scattering and invasion. We identified complementary targets and drugs that allow for the induction of TJSR without stimulating RhoC. Conclusions Our finding that MLN4924 acts as a mechanotherapeutic opens new ways to improve the efficacy of neddylation inhibition as an anticancer approach. Graphical Abstract

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Section: Resultsmentioning

confidence: 99%

Mechanical stress shapes the cancer cell response to neddylation inhibition

Mittler

Obeïd

Haguet

et al. 2022

J Exp Clin Cancer Res

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“…Notably, up-regulation of BCAR1 can alter the morphology of breast epithelial cell resulting in that the occurrence and development of breast cancer, which is exactly consistent with our result that the expression of BCAR1 was clearly upregulated in M1 patients compared with M0 samples (Figure 8C). Hence, BCAR1 might play a key role in the occurrence and development of tumor and could be used as a reliably metastatic biomarker (34,35). PANX2, whose full name is pannexin 2, encoding the protein pannexin 2, belonging to the innexin family, is the structural components of gap junctions (36).…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of ceRNA Network Reveals Prognostic and Metastasis Associated Biomarkers in Breast Cancer

Zheng

et al. 2021

Front. Oncol.

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BackgroundBreast cancer is a malignancy and lethal tumor in women. Metastasis of breast cancer is one of the causes of poor prognosis. Increasing evidences have suggested that the competing endogenous RNAs (ceRNAs) were associated with the metastasis of breast cancer. Nonetheless, potential roles of ceRNAs in regulating the metastasis of breast cancer remain unclear.MethodsThe RNA expression (3 levels) and follow-up data of breast cancer and noncancerous tissue samples were downloaded from the Cancer Genome Atlas (TCGA). Differentially expressed and metastasis associated RNAs were identified for functional analysis and constructing the metastasis associated ceRNA network by comprehensively bioinformatic analysis. The Kaplan-Meier (K-M) survival curve was utilized to screen the prognostic RNAs in metastasis associated ceRNA network. Moreover, we further identified the metastasis associated biomarkers with operating characteristic (ROC) curve. Ultimately, the data of Cancer Cell Line Encyclopedia (CCLE, https://portals.broadinstitute.org/ccle) website were selected to obtained the reliable metastasis associated biomarkers.Results1005 mRNAs, 22 miRNAs and 164 lncRNAs were screened as differentially expressed and metastasis associated RNAs. The results of GO function and KEGG pathway enrichment analysis showed that these RNAs are mainly associated with the metabolic processes and stress responses. Next, a metastasis associated ceRNA (including 104 mRNAs, 19 miRNAs, and 16 lncRNAs) network was established, and 12 RNAs were found to be related to the overall survival (OS) of patients. In addition, 3 RNAs (hsa-miR-105-5p, BCAR1, and PANX2) were identified to serve as reliable metastasis associated biomarkers. Eventually, the results of mechanism analysis suggested that BCAR1 might promote the metastasis of breast cancer by facilitating Rap 1 signaling pathway.ConclusionIn the present research, we identified 3 RNAs (hsa-miR-105-5p, BCAR1 and PANX2) might associated with prognosis and metastasis of breast cancer, which might be provide a new perspective for metastasis of breast cancer and contributed to the treatment of breast cancer.

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“…PRK3 also co-localizes with the actin cytoskeleton remodelling adaptor protein p130 cas in pro-invasive cell structures and both are overexpressed in breast and prostate cancer. PRK3 phosphorylates p130 cas and this is required for PRK3-dependent malignant growth and invasiveness of MEFs expressing constitutively active c-Src [ 123 ]. PRK3, therefore, drives metastasis, a hallmark of cancer.…”

Section: Role In Diseasementioning

confidence: 99%

The structure and function of protein kinase C-related kinases (PRKs)

Sophocleous

Owen

Mott

2021

Biochemical Society Transactions

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The protein kinase C-related kinase (PRK) family of serine/threonine kinases, PRK1, PRK2 and PRK3, are effectors for the Rho family small G proteins. An array of studies have linked these kinases to multiple signalling pathways and physiological roles, but while PRK1 is relatively well-characterized, the entire PRK family remains understudied. Here, we provide a holistic overview of the structure and function of PRKs and describe the molecular events that govern activation and autoregulation of catalytic activity, including phosphorylation, protein interactions and lipid binding. We begin with a structural description of the regulatory and catalytic domains, which facilitates the understanding of their regulation in molecular detail. We then examine their diverse physiological roles in cytoskeletal reorganization, cell adhesion, chromatin remodelling, androgen receptor signalling, cell cycle regulation, the immune response, glucose metabolism and development, highlighting isoform redundancy but also isoform specificity. Finally, we consider the involvement of PRKs in pathologies, including cancer, heart disease and bacterial infections. The abundance of PRK-driven pathologies suggests that these enzymes will be good therapeutic targets and we briefly report some of the progress to date.

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The interaction of p130Cas with PKN3 promotes malignant growth

Cited by 16 publications

References 61 publications

Mechanical stress shapes the cancer cell response to neddylation inhibition

Mechanical stress shapes the cancer cell response to neddylation inhibition

Integrated Analysis of ceRNA Network Reveals Prognostic and Metastasis Associated Biomarkers in Breast Cancer

The structure and function of protein kinase C-related kinases (PRKs)

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