Dual Blockade of PKA and NF-κB Inhibits H2 Relaxin-Mediated Castrate-Resistant Growth of Prostate Cancer Sublines and Induces Apoptosis

Ruth Louise Vinall, Christopher M. Mahaffey, Ryan R. Davis, Zunping Luo, Regina F Gandour-Edwards, Paramita M Ghosh, Clifford G Tepper, Ralph W deVere White

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

We previously demonstrated that H2 relaxin (RLN2) facilitates castrate-resistant (CR) growth of prostate cancer (CaP) cells through PI3K/Akt/β-catenin-mediated activation of the androgen receptor (AR) pathway. As inhibition of this pathway caused only ~50% reduction in CR growth, the goal of the current study was to identify additional RLN2-activated pathways that contribute to CR growth. Next-generation sequencing-based transcriptome and gene ontology analyses comparing LNCaP stably transfected with RLN2 versus LNCaP-vector identified differential expression of genes associated with cell proliferation (12.7% of differentially expressed genes), including genes associated with the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) and nuclear factor-kappaB (NF-κB) pathways. Subsequent molecular analyses confirmed that the cAMP/PKA and NF-κB pathways play a role in facilitating H2 relaxin-mediated CR growth of CaP cells. Inhibition of PKA-attenuated RLN2-mediated AR activity inhibited proliferation and caused a small but significant increase in apoptosis. Combined inhibition of the PKA and NF-κB signaling pathways via inhibition of PKA and Akt induced significant apoptosis and dramatically reduced clonogenic potential, outperforming docetaxel, the standard of care treatment for CR CaP. Immunohistochemical analysis of tissue microarrays in combination with multispectral quantitative imaging comparing RLN2 levels in patients with benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia, and CaP determined that RLN2 is significantly upregulated in CaP vs BPH (p = 0.002). The combined data indicate RLN2 overexpression is frequent in CaP patients and provides a growth advantage to CaP cells. A near-complete inhibition of RLN2-induced CR growth can be achieved by simultaneous blockade of both pathways.

Original languageEnglish (US)
Pages (from-to)224-238
Number of pages15
JournalHormones and Cancer
Volume2
Issue number4
DOIs
StatePublished - Aug 2011

Fingerprint

Relaxin
Prostatic Neoplasms
Apoptosis
Growth
Androgen Receptors
Prostatic Hyperplasia
docetaxel
Cyclic AMP-Dependent Protein Kinases
Cyclic AMP
Tissue Array Analysis
Prostatic Intraepithelial Neoplasia
Catenins
Gene Ontology
Standard of Care
Phosphatidylinositol 3-Kinases
Transcriptome
Genes
Cell Proliferation
Gene Expression

Keywords

  • Androgen receptor
  • Castrate-resistant prostate cancer
  • Cyclic AMP
  • H2 relaxin
  • NF-kappaB
  • Protein kinase A

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Endocrine and Autonomic Systems

Cite this

Dual Blockade of PKA and NF-κB Inhibits H2 Relaxin-Mediated Castrate-Resistant Growth of Prostate Cancer Sublines and Induces Apoptosis. / Vinall, Ruth Louise; Mahaffey, Christopher M.; Davis, Ryan R.; Luo, Zunping; Gandour-Edwards, Regina F; Ghosh, Paramita M; Tepper, Clifford G; deVere White, Ralph W.

In: Hormones and Cancer, Vol. 2, No. 4, 08.2011, p. 224-238.

Research output: Contribution to journalArticle

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abstract = "We previously demonstrated that H2 relaxin (RLN2) facilitates castrate-resistant (CR) growth of prostate cancer (CaP) cells through PI3K/Akt/β-catenin-mediated activation of the androgen receptor (AR) pathway. As inhibition of this pathway caused only ~50{\%} reduction in CR growth, the goal of the current study was to identify additional RLN2-activated pathways that contribute to CR growth. Next-generation sequencing-based transcriptome and gene ontology analyses comparing LNCaP stably transfected with RLN2 versus LNCaP-vector identified differential expression of genes associated with cell proliferation (12.7{\%} of differentially expressed genes), including genes associated with the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) and nuclear factor-kappaB (NF-κB) pathways. Subsequent molecular analyses confirmed that the cAMP/PKA and NF-κB pathways play a role in facilitating H2 relaxin-mediated CR growth of CaP cells. Inhibition of PKA-attenuated RLN2-mediated AR activity inhibited proliferation and caused a small but significant increase in apoptosis. Combined inhibition of the PKA and NF-κB signaling pathways via inhibition of PKA and Akt induced significant apoptosis and dramatically reduced clonogenic potential, outperforming docetaxel, the standard of care treatment for CR CaP. Immunohistochemical analysis of tissue microarrays in combination with multispectral quantitative imaging comparing RLN2 levels in patients with benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia, and CaP determined that RLN2 is significantly upregulated in CaP vs BPH (p = 0.002). The combined data indicate RLN2 overexpression is frequent in CaP patients and provides a growth advantage to CaP cells. A near-complete inhibition of RLN2-induced CR growth can be achieved by simultaneous blockade of both pathways.",
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AU - Davis, Ryan R.

AU - Luo, Zunping

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