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Torc1/Torc2 inhibitor, Palomid 529, enhances radiation response modulating CRM1‐mediated survivin function and delaying DNA repair in prostate cancer models
Author(s) -
Gravina Giovanni Luca,
Marampon Francesco,
Sherris David,
Vittorini Francesca,
Cesare Ernesto Di,
Tombolini Vincenzo,
Lenzi Andrea,
Jannini Emmanuele A.,
Festuccia Claudio
Publication year - 2014
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.22804
Subject(s) - survivin , radiosensitizer , dna damage , cancer research , dna repair , mitotic catastrophe , ku70 , biology , parp inhibitor , radioresistance , apoptosis , chemistry , poly adp ribose polymerase , medicine , radiation therapy , cell culture , dna , genetics , polymerase
BACKGROUND P529, a Torc1/Torc2 inhibitor, has demonstrated its potential as a radiosensitizer. However the molecular mechanisms underlying this phenomenon still need to be elucidated. Aim of this study is to dissect molecular mechanisms regulating the radiosensitizing properties of P529 in a wide panel of prostate cancer models. METHODS Six tumor cell lines and xenograft models were used for in vitro and in vivo studies. Clonogenic survival, apoptotic, autophagic, and senescence assays were used to examine the effects of ionizing radiation (IR) alone and in combination with P529. CRM1, survivin, GSK‐3β, and DNA‐DSBs expression and modulation, upon P529 and RT, were monitored by western blot. In vivo treatment response upon P529, irradiation or combination of P529 with IR was monitored by tumor volume, time to progression (TTP), and immunohistochemical analysis. RESULTS P529 treatment induced significantly more apoptosis and DNA double‐strand break (DSB) when combined with radiotherapy resulting in cellular radiosensitization and growth delay of irradiated tumor xenografts. Upon P529 treatment Rad51, DNA‐PKcs, and Ku70 protein expression was downregulated, indicating delayed DNA double‐strand damage repair. The radiosensitizing properties of P529 were partially linked to GSK‐3β, cyclin‐D1, and c‐myc modulation with associated inhibition of CRM1‐mediated nuclear export of survivin. Importantly, autophagy and tumor senescence were involved in the enhanced P529 radioresponse. CONCLUSIONS Impaired DNA double‐strand damage repair, inhibition of CRM1‐mediated nuclear export of survivin, modulation of cyclin‐D1 and c‐myc with associated pro‐apoptotic and autophagic and senescent events explain the radiosensitizing properties of P529 in preclinical models of prostate cancer. Prostate 74:852–868, 2014 . © 2014 Wiley Periodicals, Inc.