Prolonged androgen deprivation leads to overexpression of calpain 2: Implications for prostate cancer progression

Liu, Tiancheng; Mendes, Desiree E.; Berkman, Clifford E.

doi:10.3892/ijo.2013.2196

Cited by 26 publications

(22 citation statements)

References 34 publications

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“…Recent studies have reported that Ca o 2+ stimulates the CaR leading to Rho activation, actin cytoskeleton remodeling, cell shape changes, formation of a migrating front (leading edge) and altered adhesion [18–20, 46]. Filamin A is an actin binding protein and the C-terminal portion of filamin A acts as a GTPase docking site by binding several RhoGTPases including RalA, Cdc42, Rac1, and RhoA [48, 55] which regulate cytoskeleton reorganization and cell migration.…”

Section: Discussionmentioning

confidence: 99%

Signaling regulation and role of filamin A cleavage in Ca2+-stimulated migration of androgen receptor-deficient prostate cancer cells

2016

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Ca2+, a ubiquitous cellular signal, and filamin A, an actin-binding protein, play an important role in the regulation of cell adhesion, shape and motility. Using transwell filters to analyze cell migration, we found that extracellular Ca2+ (Cao2+) promotes the migration of androgen receptor (AR)-deficient and highly metastatic prostate cancer cell lines (DU145 and PC-3) compared to AR-positive and relatively less metastatic prostate cancer cells (LNCaP). Furthermore, we found that expression of filamin A is up-regulated in DU145 and PC-3 cells, and that Cao2+ significantly induces the cleavage of filamin A. Silencing expression of Ca2+-sensing receptor (CaR) and p115RhoGEF, and treating with leupeptin, a protease inhibitor, and ALLM, a calpain specific inhibitor, we further demonstrate that Cao2+-induced filamin A cleavage occurs via a CaR- p115RhoGEF-calpain dependent pathway. Our data show that Cao2+ via CaR- mediated signaling induces filamin A cleavage and promotes the migration in AR-deficient and highly metastatic prostate cancer cells.

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Section: Discussionmentioning

confidence: 99%

Signaling regulation and role of filamin A cleavage in Ca2+-stimulated migration of androgen receptor-deficient prostate cancer cells

2016

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“…For example, recent research suggests the role of calpain-1 in proteolytic cleavage of β-catenin which leads to aberrant stabilization of the protein and increased tumorigenic potential in cancer cells [26]. Overexpression and enhanced activity of calpain-2 also induces an increase in the fragmental cleavage of AR and FlnA, which may contribute to the development of an aggressive phenotype of prostate cancer [27]. Recent research suggest that calpain-4 promotes cell spreading and migration by disassembling focal adhesions in the trailing edge of cells [28].…”

Section: Discussionmentioning

confidence: 99%

Elevated Expression of Calpain-4 Predicts Poor Prognosis in Patients with Gastric Cancer after Gastrectomy

Peng

Min

Song

et al. 2016

IJMS

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Calpain-4 belongs to the calpain family of calcium-dependent cysteine proteases, and functions as a small regulatory subunit of the calpains. Recent evidence indicates that calpain-4 plays critical roles in tumor migration and invasion. However, the roles of calpain-4 in gastric tumorigenesis remain poorly understood. Herein, we examined calpain-4 expression by immunohistochemical staining on tissue microarrays containing tumor samples of 174 gastric cancer patients between 2004 and 2008 at a single center. The Kaplan-Meier method was used to compare survival curves, and expression levels were correlated to clinicopathological factors and overall survival. Our data demonstrated that calpain-4 was generally increased in gastric cancer cell lines and primary tumor tissues. High expression of calpain-4 was positively associated with vessel invasion, lymph node metastasis, and advanced TNM (Tumor Node Metastasis) stage. Multivariate analysis identified calpain-4 as an independent prognostic factor for poor prognosis. A predictive nomogram integrating calpain-4 expression with other independent prognosticators was constructed, which generated a better prognostic value for overall survival of gastric cancer patients than a TNM staging system. In conclusion, calpain-4 could be regarded as a potential prognosis indicator for clinical outcomes in gastric cancer.

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“…However, patients on ADT will eventually progress to castration-resistant prostate cancer (CRPC), which is currently incurable [42]. Long-term androgen deprivation will result in increased expression of FlnA [43], but once nuclear localized, FlnA can enhance androgen responsiveness and sensitize CRPC cells to ADT by inducing apoptosis in CRPC cells during ADT, identifying it is a treatment tool in advanced prostate cancer [44]. Mooso et al [44] Abbreviations: IHC Immunohistochemistry PMSA Prostate-specific membrane antigen hAR Human androgen receptor PrP Prion protein EGFR Epidermal growth factor receptor a Only part of researches in prostate cancer and breast cancer evaluate the differences that arise from the localization of the protein b Animal studies of FlnA were only carried out in melanoma.…”

Section: Prostate Cancermentioning

confidence: 99%

Filamin A: Insights into its Exact Role in Cancers

Shao

Zhang

Zhao

et al. 2015

Pathol. Oncol. Res.

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Filamin A (FlnA) is a well-known actin cross-linking protein. It serves as a scaffold for over 90 binding partners and involves in multiple cell functions, of which cell migration and adhesion is especially critical. Recently, its role in the cell has come under scrutiny for FlnA's involvement in cancer development. Originally revealed as a cancer-promoting protein, FlnA actually plays a dual role in cancers. When localized to the cytoplasm, FlnA has a tumor-promoting effect by interacting with signaling molecules. While once localized to the nucleus, it may act to suppress tumor growth and inhibit metastasis by interacting with transcription factors. Thus drugs that can cause FlnA to transpose from cytoplasm to nucleus could be a promising treatment for cancers. Study to this end is on the way in prostate cancer and the results are encouraging. FlnA has been studied in large categories of cancers, such as prostate cancer, breast cancer, melanoma, lung cancer, etc. However, most studies did not evaluate the differences that arise from the localization of the protein, which was a great pity! What's more, although FlnA's is undoubtedly important in cancer invasion and metastasis, both preclinical and clinical researches are very rare in some highly metastatic cancers, such as pancreatic cancer. In this mini-review, we give a comprehensive summary of FlnA' s expression in cancers. Where available, we also indicate the correlation of FlnA with cancer stages and patient prognosis, and clarify its localization (nucleus/cytoplasm) and its dual role (promote/suppress) in different cancers.

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Prolonged androgen deprivation leads to overexpression of calpain 2: Implications for prostate cancer progression

Cited by 26 publications

References 34 publications

Signaling regulation and role of filamin A cleavage in Ca2+-stimulated migration of androgen receptor-deficient prostate cancer cells

Signaling regulation and role of filamin A cleavage in Ca2+-stimulated migration of androgen receptor-deficient prostate cancer cells

Elevated Expression of Calpain-4 Predicts Poor Prognosis in Patients with Gastric Cancer after Gastrectomy

Filamin A: Insights into its Exact Role in Cancers

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