Overexpression of the VSSC‐associated CAM, beta‐2, enhances LNCaP cell metastasis associated behavior

Jansson, Keith H.; Lynch, Jill E.; Lepori-Bui, Nadia; Czymmek, Kirk J.; Duncan, Randall L.; Sikes, Robert A.

doi:10.1002/pros.21512

Cited by 33 publications

(57 citation statements)

References 55 publications

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“…After a further cultivation of 48 h, antibiotic selection of the transduced cells in the presence or absence of AR ligands was performed for 10-15 days. The resistant cells were fixed with 1 % glutaraldehyde, stained with 0.1 % crystal violet as an indirect measure of cell number, and the cell-associated crystal violet in dried plates was solubilized with Sørenson's solution as described [24]. Absorbance was measured at 590 nm.…”

Section: Growth Assaysmentioning

confidence: 99%

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A novel crosstalk between the tumor suppressors ING1 and ING2 regulates androgen receptor signaling

et al. 2016

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Section: Growth Assaysmentioning

confidence: 99%

“…The scratch assays were performed according to Jansson et al [24]. The images acquired were further analyzed quantitatively by using TScratch computing software [25].…”

Section: Scratch Assaysmentioning

confidence: 99%

A novel crosstalk between the tumor suppressors ING1 and ING2 regulates androgen receptor signaling

et al. 2016

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“…SCN1B and SCN2B expression are associated with metastatic potential in prostate cancer cells (Diss et al, 2008; Jansson et al, 2012). However, studies of the invasive potential of SCN1B -expressing breast cancer in vitro have been contradicted by in vivo studies.…”

Section: Pathophysiological Roles Of Vgscsmentioning

confidence: 99%

Voltage-Gated Na⁺Channels: Not Just for Conduction

Kruger

Isom

2016

Cold Spring Harb Perspect Biol

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Voltage-gated sodium channels (VGSCs), composed of a pore-forming α subunit and up to two associated β subunits, are critical for the initiation of the action potential in excitable tissues. Building upon the monumental discovery and description of sodium current in 1952, intrepid researchers described the voltage-dependent gating mechanism, selectivity of the channel, and general structure of the VGSC channel. Recently, crystal structures of bacterial VGSC α subunits have confirmed many of these studies and provided new insights into VGSC function. VGSC β subunits, first cloned in 1992, modulate sodium current but also have non-conducting roles as cell adhesion molecules and function in neurite outgrowth and neuronal pathfinding. Mutations in VGSC α and β genes are associated with diseases caused by dysfunction of excitable tissues such as epilepsy. Due to the multigenic and drug-resistant nature of some of these diseases, induced pluripotent stem cells and other novel approaches are being used to screen for new drugs and further understand how mutations in VGSC genes contribute to pathophysiology. Voltage-gated sodium channels (VGSCs) conduct inward current that depolarizes the plasma membrane and initiates the action potential (AP) in excitable cells, including neurons, cardiomyocytes, and skeletal muscle cells. Because of the intrinsic link between VGSCs and cellular excitability, it is not surprising that mutations in VGSC genes are linked with epilepsy, cardiac arrhythmia, neuropathic pain, migraine, and neuromuscular disorders (Table 1). The goal of this review is to provide an overview of critical discoveries in VGSC physiology and discuss the challenges of studying VGSCs in disease, including some of the exciting techniques to address these challenges.

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“…Beta-2 mRNA [61], [62] and protein are expressed in PCa cells lines with beta-2 protein production exhibiting a significant increase in highly aggressive cells relative to weakly aggressive cells [62]. When beta-2 is overexpressed in weakly aggressive LNCaP cells, their metastasis-associated behavior in vitro is enhanced but their subcutaneous tumor volume is reduced drastically [62].…”

Section: Introductionmentioning

confidence: 99%

“…When beta-2 is overexpressed in weakly aggressive LNCaP cells, their metastasis-associated behavior in vitro is enhanced but their subcutaneous tumor volume is reduced drastically [62]. Using beta-2 overexpressing LNCaP cells (2BECFP), vector control LNCaP cells (LNECFP), and highly aggressive C4-2B4 cells, we examined whether the expression of beta-2 altered the neurotropic behavior of PCa cells using a novel ex vivo spinal co-culture system, in vitro functional metastatic assays, and atomic force microscopy.…”

Section: Introductionmentioning

confidence: 99%

Identification of Beta-2 as a Key Cell Adhesion Molecule in PCa Cell Neurotropic Behavior: A Novel Ex Vivo and Biophysical Approach

et al. 2014

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Prostate cancer (PCa) is believed to metastasize through the blood/lymphatics systems; however, PCa may utilize the extensive innervation of the prostate for glandular egress. The interaction of PCa and its nerve fibers is observed in 80% of PCa and is termed perineural invasion (PNI). PCa cells have been observed traveling through the endoneurium of nerves, although the underlying mechanisms have not been elucidated. Voltage sensitive sodium channels (VSSC) are multimeric transmembrane protein complexes comprised of a pore-forming α subunit and one or two auxiliary beta (β) subunits with inherent cell adhesion molecule (CAM) functions. The beta-2 isoform (gene SCN2B) interacts with several neural CAMs, while interacting putatively with other prominent neural CAMs. Furthermore, beta-2 exhibits elevated mRNA and protein levels in highly metastatic and castrate-resistant PCa. When overexpressed in weakly aggressive LNCaP cells (2BECFP), beta-2 alters LNCaP cell morphology and enhances LNCaP cell metastasis associated behavior in vitro. We hypothesize that PCa cells use beta-2 as a CAM during PNI and subsequent PCa metastasis. The objective of this study was to determine the effect of beta-2 expression on PCa cell neurotropic metastasis associated behavior. We overexpressed beta-2 as a fusion protein with enhanced cyan fluorescence protein (ECFP) in weakly aggressive LNCaP cells and observed neurotropic effects utilizing our novel ex vivo organotypic spinal cord co-culture model, and performed functional assays with neural matrices and atomic force microscopy. With increased beta-2 expression, PCa cells display a trend of enhanced association with nerve axons. On laminin, a neural CAM, overexpression of beta-2 enhances PCa cell migration, invasion, and growth. 2BECFP cells exhibit marked binding affinity to laminin relative to LNECFP controls, and recombinant beta-2 ectodomain elicits more binding events to laminin than BSA control. Functional overexpression of VSSC beta subunits in PCa may mediate PCa metastatic behavior through association with neural matrices.

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Overexpression of the VSSC‐associated CAM, beta‐2, enhances LNCaP cell metastasis associated behavior

Abstract: Functional overexpression of VSSC β-subunits in PCa may be one mechanism leading to increased metastatic behavior while decreasing the ability to form localized tumor masses.

Cited by 33 publications

References 55 publications

A novel crosstalk between the tumor suppressors ING1 and ING2 regulates androgen receptor signaling

A novel crosstalk between the tumor suppressors ING1 and ING2 regulates androgen receptor signaling

Voltage-Gated Na⁺Channels: Not Just for Conduction

Identification of Beta-2 as a Key Cell Adhesion Molecule in PCa Cell Neurotropic Behavior: A Novel Ex Vivo and Biophysical Approach

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Overexpression of the VSSC‐associated CAM, beta‐2, enhances LNCaP cell metastasis associated behavior

Abstract: Functional overexpression of VSSC β-subunits in PCa may be one mechanism leading to increased metastatic behavior while decreasing the ability to form localized tumor masses.

Cited by 33 publications

References 55 publications

A novel crosstalk between the tumor suppressors ING1 and ING2 regulates androgen receptor signaling

A novel crosstalk between the tumor suppressors ING1 and ING2 regulates androgen receptor signaling

Voltage-Gated Na+Channels: Not Just for Conduction

Identification of Beta-2 as a Key Cell Adhesion Molecule in PCa Cell Neurotropic Behavior: A Novel Ex Vivo and Biophysical Approach

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Voltage-Gated Na⁺Channels: Not Just for Conduction