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Non-androgen Signaling Pathways in Castration-Resistant Prostate Cancer

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Managing Metastatic Prostate Cancer In Your Urological Oncology Practice

Abstract

Prostate cancer (PCa), while initially androgen-sensitive, the lethal form of the disease inevitably progresses to hormone refractory or castration-resistant state and accounts for vast majority of mortality among PCa patients. During the transition from the hormone naïve disease into CRPC, the progression of PCa cells can be driven by alternative (non-androgen) signaling pathways. Upregulation of ligands, receptors and intracellular signaling molecules along with activating mutations of proto-oncogenes and/or suppression of tumor suppressor genes are the major causes of the deregulation of these alternative pathways. In addition, loss of negative feedback mechanism of the signal cascades further amplifies the effects of the pathways and thus contributing to the emergence of CRPC. This chapter covers studies investigating the potential involvement of non-androgen signaling pathways in PCa and the current strategies employed in PCa cell lines, animal models and clinical trials for controlling these aberrant signaling pathways. The understanding of non-androgen signaling pathway target(s) in CRPC could provide novel biomarkers and newer strategies in management of metastatic PCa.

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Abbreviations

ADT:

Androgen deprivation therapy

Akt:

AKR mouse strain thymoma

AR:

Androgen receptor

BAD:

Bcl-2 associated death promoter

Bcl-2:

B-cell lymphoma-2

BRCA1:

Breast cancer susceptibility type 1

Ca2+ :

Calcium++

CAMs:

Cell-surface adhesion molecules

CaMK:

Ca2+/calmodulin-dependent protein kinase

cAMP:

cyclic Adenosine Mono-Phosphate

CRPC:

Castration-resistant prostate cancer

Dhh:

Desert hedgehog

DKKs:

Dickkopf family members

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

EGFR:

EGF receptor

EMT:

Epithelial-mesenchymal transition

ET-1:

Endothelin 1

ET1AR:

ET-1A receptor

FISH:

Fluorescence in situ hybridization

FGF:

Fibroblast growth factor

FGFRs:

FGF receptors

FSH:

Follicle stimulating hormone

GF:

Growth factor

GFRs:

GF receptors

gp130:

Glycoprotein 130

GPCR:

G-protein coupled receptor

HER2:

Human EGF receptor 2

Hh:

Hedgehog

HSP 27:

Heat shock protein 27

IGF:

Insulin-like growth factor

IGF-IR:

IGF-I receptor

IGFBPs:

IGF binding proteins

Ihh:

Indian hedgehog

ILs:

Interleukins

IP3 :

Inositol triphosphate

IWPs:

Inhibitors of Wnt productions

IWRs:

Inhibitor of Wnt responses

JAK:

Janus kinase

JNK:

c-Jun N-terminal Kinase

LPA:

Lysophosphatidic acid

LRP5/6:

Lipoprotein receptor–related proteins 5 and 6

MAPK:

Mitogen-activated protein kinase

Mcl-1:

Myeloid cell leukemia 1

mCRPC:

Metastatic CRPC

MEK:

MAPK/ERK kinase

MMPs:

Matrix metalloproteinases

mRNA:

Messenger ribonucleic acid

mTOR:

Mammalian target of rapamycin or mechanistic target of rapamycin

NSAIDs:

Non-steroidal anti-inflammatory drugs

NSE:

Neuron-specific enolase

p42ERK:

p42 (42 kDa) extracellular-signal-regulated kinase

p70S6K :

p70 (70 kDa) S6 ribosomal kinase

PCa:

Prostate cancer

PGE2:

Prostaglandin E2

PI3K:

Phosphoinositide 3-kinase

PIN:

Prostatic intraepithelial neoplasia

PIP2 :

phosphatidylinositol (4,5) bisphosphate

PIP3 :

phosphatidylinositol (3,4,5) trisphosphate

PKD1:

Protein kinase D1

PLC:

Phospolipase C

PSA:

Prostate-specific antigen

PTEN:

Phosphatase and tensin homologue deleted on chromosome ten

Ptch:

Human pathced

Raf:

Rapidly accelerated fibrosarcoma

Ras:

Rat sarcoma

RGD:

Arginine (R)-Glycine (G)-Aspartate (D) sequence

RIN:

Ras-like protein in neurons

RKIP:

Raf kinase inhibitor protein

RTK:

Receptor tyrosine kinase

Shh:

Sonic hedgehog

SMAD:

Sma (small)/Mad (Mothers against decapentaplegic) homology

Smo:

Patched of smoothened

SFRP:

Secreted frizzled-related protein family

STAT:

Signal transducer and activator of transcription

TGFβ:

Transforming growth factor-β

TβRII:

TGFβ receptor-II

TRAMP:

Transgenic adenocarcinoma of mouse prostate

VEGF:

Vascular endothelial growth factor

WIF1:

Wnt inhibitory factor 1

Wnt:

Wingless gene (Wg) homolog of int-1 (integration-1) or Wingless-related integration site

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  1. Institute of Regenerative Medicine, Wake Forest University Health Science, 391 Technology Way, 27101, Winston-Salem, NC, USA

    Sivanandane Sittadjody & Bita NickKolgh

  2. Winston-Salem, 27127, NC, USA

    Thilakavathy Thangasamy

  3. Department of Urology, Cancer Biology, Institute of Regenerative Medicine, Wake Forest University School of Medicine, W.G. (Bill) Hefner VA Medical Center, Medical Center Blvd, 27157-1094, Winston-Salem, NC, USA

    K. C. Balaji

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    K.C Balaji

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Sittadjody, S., Thangasamy, T., NickKolgh, B., Balaji, K.C. (2016). Non-androgen Signaling Pathways in Castration-Resistant Prostate Cancer. In: Balaji, K. (eds) Managing Metastatic Prostate Cancer In Your Urological Oncology Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-31341-2_4

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