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Emerging roles of radioresistance in prostate cancer metastasis and radiation therapy

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Abstract

Radiation therapy (RT) continues to be one of the most popular treatment options for localized prostate cancer (CaP). Local CaP recurrence after RT is a pattern of treatment failure attributable to radioresistance of cancer cells. One major obstacle to RT is that there is a limit to the amount of radiation that can be safely delivered to the target organ. Recent results indicate that phosphoinositide 3-kinase (PI3K)/Akt/phosphatase and tensin homolog (PTEN)/mammalian target of rapamycin (mTOR) signaling pathway, autophagy, epithelial–mesenchymal transition (EMT) and cancer stem cells (CSCs) are involved in CaP metastasis and radioresistance. Emerging evidence also suggests that combining a radiosensitizer with RT increases the efficacy of CaP treatment. Understanding the mechanisms of radioresistance will help to overcome recurrence after RT in CaP patients and prevent metastasis. In this review, we discuss the novel findings of PI3K/Akt/PTEN/mTOR signaling pathway, autophagy, EMT and CSCs in the regulation of CaP metastasis and radioresistance, and focus on combination of radiosensitizers with RT in the treatment of CaP in preclinical studies to explore novel approaches for future clinical trials.

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Abbreviations

AD:

Androgen deprivation

Ad-E2F1:

Adenoviral-mediated E2F1

ALDH:

Aldehyde dehydrogenase

AR:

Androgen receptor

AS:

Antisense

ASODN:

Antisense Bcl-2 oligodeoxynucleotide

ATM:

Ataxia telangiectasia mutated

ATO:

Arsenic trioxide

BCR:

Biochemical recurrence

BCRP:

Breast cancer resistance protein

BCSCs:

Breast cancer stem cells

bHLH:

Basic helix-loop-helix

β-lap:

β-lapachone

CaP:

Prostate cancer

CD44v:

CD44 variants

CK:

Cytoskeleton

COX-2:

Cyclooxygenase-2

CRPC:

Castration-resistant prostate cancer

CSCs:

Cancer stem cells

CTCs:

Circulating tumor cells

DCA:

Dichloroacetate

DHMEQ:

Dehydroxymethyl derivative of epoxyquinomicin

Didox:

DX; 3,4-dihydroxybenzohydroxamic acid

DSBs:

Double-strand breaks

EBRT:

External beam radiotherapy

EGFR:

Epidermal growth factor receptor

EMT:

Epithelial–mesenchymal transition

EpCAM:

Epithelial cell adhesion molecule

ER:

Endoplasmic reticulum

FACS:

Fluorescence-activated cell sorting

FGFR2IIIb:

Fibroblast growth factor receptor 2IIIb

FLT3:

Fms-like tyrosine kinase-3

GKS:

Gamma knife surgery

HCC:

Hepatocellular carcinoma

HDACIs:

Histone deacetylase inhibitors

HMAF:

Hydroxymethylacylfulvene

HMG-CoA:

Hydroxyl-3-methylglutaryl coenzyme A

HNSCC:

Head and neck squamous cell carcinoma

IGF1R:

Insulin-like growth factor-type 1 receptor

IGRT:

Image-guided radiation therapy

IMRT:

Intensity modulated radiation therapy

IR:

Ionizing radiation

MAb:

Monoclonal antibody

MACS:

Magnetic activated cell sorting

MAPK:

Mitogen-activated protein kinase

MET:

Mesenchymal to epithelial transition

miRNA:

MicroRNA

MP:

Monascuspiloin

MRP-1:

Multidrug resistance protein 1

mTOR:

Mammalian target of rapamycin

NF-kB:

Nuclear factor-κB

NOD/SCID:

Non-obese diabetic/severe combined immunodeficiency

NO-NSAIDs:

Nitric oxide donating nonsteroidal anti-inflammatory drugs

NQO1:

NAD(P)H:quinone oxidoreductase 1

NSAIDs:

Nonsteroidal anti-inflammatory drugs

P529:

Palomid 529

p-Akt:

Phospho-Akt

PAP:

Prostatic acid phosphatise

PCR:

Polymerase chain reaction

PDGF:

Platelet-derived growth factor

PDK:

Pyruvate dehydrogenase kinase

PI3K:

Phosphoinositide 3-kinase

PKB:

Protein kinase B

PSA:

Prostate-specific antigen

PtdIns(3,4)P2:

Phosphatidylinositol 3,4-bisphosphate

PtdIns(3,4,5)P3:

Phosphatidylinositol 3,4,5-trisphosphate

PtdIns(4)P:

Phosphatidylinositol 4-phosphate

PtdIns(4,5)P2:

Phosphatidylinositol 4,5-bisphosphate

PTEN:

Phosphatase and tensin homolog

RP:

Radical prostatectomy

RR:

Radioresistant

RT:

Radiation therapy

SAHA:

Suberoylanilide hydroxamic acid

s.c:

Subcutaneous

siRNA:

Small interfering RNA

SLD:

Sublethal radiation damage

SSE:

Sodium selenite

TGF-β:

Transforming growth factor-β

TKIs:

Tyrosine kinase inhibitors

TSC2:

Tuberous sclerosis complex 2

VPA:

Valproic acid

VEGFR:

Vascular endothelial growth factor receptor

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Acknowledgments

Our prostate cancer radiation research project was supported in part by a NH&MRC Career Development Fellowship; Cancer Research Trust Fund at Cancer Care Centre, St George Hospital; and Prostate and Breast Cancer Foundation. The authors thank the technical support from Mr Ken Hopper, Mr Ese Enari, Mr Alex Wallace, and Mr Peter Treacy from the Cancer Care Centre, Sydney, Australia.

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Authors and Affiliations

  1. Cancer Care Centre and Prostate Cancer Institute, St. George Hospital, Gray St Kogarah, Sydney, NSW, 2217, Australia

    Lei Chang, Peter H. Graham, Jingli Hao, Joseph Bucci, John H. Kearsley & Yong Li

  2. St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW, 2052, Australia

    Lei Chang, Peter H. Graham, Jingli Hao, Joseph Bucci, Paul J. Cozzi, John H. Kearsley & Yong Li

  3. Department of Surgery, St. George Hospital, Sydney, NSW, 2217, Australia

    Paul J. Cozzi

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  1. Lei Chang
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Correspondence to Yong Li.

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Chang, L., Graham, P.H., Hao, J. et al. Emerging roles of radioresistance in prostate cancer metastasis and radiation therapy. Cancer Metastasis Rev 33, 469–496 (2014). https://doi.org/10.1007/s10555-014-9493-5

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