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Cancer and Metastasis Reviews

, Volume 33, Issue 2–3, pp 469–496 | Cite as

Emerging roles of radioresistance in prostate cancer metastasis and radiation therapy

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

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.

Keywords

Prostate cancer Radiation therapy Radioresistance Radiosensitizer PI3K/Akt/mTOR Autophagy EMT Cancer stem cell 

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

Notes

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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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Lei Chang
    • 1
    • 2
  • Peter H. Graham
    • 1
    • 2
  • Jingli Hao
    • 1
    • 2
  • Joseph Bucci
    • 1
    • 2
  • Paul J. Cozzi
    • 2
    • 3
  • John H. Kearsley
    • 1
    • 2
  • Yong Li
    • 1
    • 2
  1. 1.Cancer Care Centre and Prostate Cancer InstituteSt. George HospitalSydneyAustralia
  2. 2.St George and Sutherland Clinical School, Faculty of MedicineUniversity of New South WalesKensingtonAustralia
  3. 3.Department of SurgerySt. George HospitalSydneyAustralia

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