PAFR selectively mediates radioresistance and irradiation-induced autophagy suppression in prostate cancer cells.

Bing Yao,Wen Wang,Mingbo Cai,Jianguo Wen,Jianhua Li,Lei Shi,Bingqian Liu,Yongde Sun,Xiang Li,Chuanchuan Ren,Yudong Wu

doi:10.18632/oncotarget.14647

Bing Yao, Wen Wang + Show 9 more

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https://doi.org/10.18632/oncotarget.14647

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Abstract

Platelet-activating factor receptor (PAFR) promotes tumorigenesis, angiogenesis and metastasis. Here, we defined the PAFR as a yielding new inhibiting target to selectively enhance the sensitivity of prostate cancer (PCa) cells to radiation. The selective responding to PAFR inhibiter may be caused by the differential expression pattern of PAFR in PCa cells. In this study, we also determined PAFR as a molecular basis by which the radiation induces autophagy suppression independent of activating mTOR pathway. PAFR can bind to the autophagy-indispensable protein Beclin 1, leading to the disability in its serine phosphorylation. The PAFR antagonist Ginkgolide B (GB) can sensitize radiotherapy by disrupting the formation of PAFR/Beclin 1 complex in PC3 and LNCaP cells, which have elevated PAFR expression after radiation exposure. Most importantly, GB efficiently radiosensitized PC3 and LNCaP tumor xenografts in vivo, and significantly reduced tumor burden. Overall, our results elucidated a significant role of GB in selectively improving the outcomes of PCa receiving radiation therapy.

Highlights

Prostate cancer (PCa) is the second leading cause of cancer deaths and the most common cancer in men in the United States [1], and its morbidity is rapidly rising in East Asian [2]
PC3 cells were treated with a series of concentrations of Platelet-activating factor receptor (PAFR) antagonist, Ginkgolide B (GB), post sham (Ctrl) and genuine irradiation
Several studies have shown that PAFR antagonists can reduce tumor metastasis in vivo [10, 21,22,23]

Summary

Introduction

Prostate cancer (PCa) is the second leading cause of cancer deaths and the most common cancer in men in the United States [1], and its morbidity is rapidly rising in East Asian [2]. Approximately 10% to 45% PCa are radioresistant either not responding or relapsing after receiving limited dose irradiation [5,6,7]. This supports that an alternative to improving efficacy of radiation would be to use radiation-sensitizer not to increase radiation dose. The abnormal expression of GPCR or aberrant activation by their ligands would initiate their signaling networks and PCa progression and resistance to anticancer treatments. Platelet-activating factor (PAR) receptor (PAFR) is one of GPCR, which can be activated by PAR. PAFR can induce chemotherapy resistance in ovarian cancer through transactivating of epidermal growth factor receptor (EGFR) [12, 13]. The biologic roles of PAFR in PCa progression and radioresistance have not been investigated

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