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 # Springer Science+Business Media New York 2014 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–mes- enchymal 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 effi- cacy 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 fu- ture 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 L. Chang : P. H. Graham : J. Hao : J. Bucci : J. H. Kearsley : Y. Li (*) Cancer Care Centre and Prostate Cancer Institute, St. George Hospital, Gray St Kogarah, Sydney, NSW 2217, Australia e-mail: y.li@unsw.edu.au L. Chang : P. H. Graham : J. Hao : J. Bucci : P. J. Cozzi : J. H. Kearsley : Y. Li St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Kensington, NSW 2052, Australia P. J. Cozzi Department of Surgery, St. George Hospital, Sydney, NSW 2217, Australia Cancer Metastasis Rev DOI 10.1007/s10555-014-9493-5