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Torc1/Torc2 inhibitor, Palomid 529, enhances radiation response modulating CRM1-mediated survivin function and
Giovanni Luca Gravina1, Francesco Marampon, David Sherris
1Division of Radiation Oncology, Department of Clinical and Applied Sciences and Biotechnologies, University of L'Aquila, L'Aquila, Italy; Department of Clinical and Applied Sciences and Biotechnologies, Laboratory of Radiobiology, University of L'Aquila, L'Aquila, Italy; Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy; Department of Clinical and Applied Sciences and Biotechnologies, School of Sexology, University of L'Aquila, L'Aquila, Italy.
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.
Insights
P529 enhances radiotherapy by impairing DNA repair and promoting apoptosis and senescence in prostate cancer models. This Torc1/Torc2 inhibitor shows promise for improving cancer treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- P529, a dual Torc1/Torc2 inhibitor, shows potential as a radiosensitizer.
- Molecular mechanisms of P529's radiosensitizing effects require elucidation.
- Prostate cancer models are utilized to investigate these mechanisms.
Purpose of the Study:
- To dissect the molecular mechanisms behind P529's radiosensitizing properties.
- To evaluate P529's efficacy in combination with radiotherapy across various prostate cancer models.
Main Methods:
- In vitro and in vivo studies using six prostate cancer cell lines and xenografts.
- Assays for clonogenic survival, apoptosis, autophagy, and senescence.
- Western blot analysis of key proteins (CRM1, survivin, GSK-3β, DNA-DSBs) and immunohistochemistry for in vivo models.
Main Results:
- P529 combined with radiotherapy significantly increased apoptosis and DNA double-strand breaks (DSBs), leading to radiosensitization and tumor growth delay.
- P529 downregulated DNA repair proteins (Rad51, DNA-PKcs, Ku70), impairing DSB repair.
- Radiosensitization was linked to GSK-3β, cyclin-D1, c-myc modulation, and inhibition of survivin nuclear export, with autophagy and senescence playing roles.
Conclusions:
- P529's radiosensitizing effects in prostate cancer are attributed to impaired DNA double-strand break repair.
- Inhibition of CRM1-mediated survivin nuclear export and modulation of cyclin-D1/c-myc contribute to these effects.
- Pro-apoptotic, autophagic, and senescent events enhance P529's radioresponse in preclinical prostate cancer models.
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