醛缩酶A(ALDOA)对前列腺癌放疗敏感性的调节作用及机制研究

Radiation resistance is a major cause of local recurrence or metastasis after radiotherapy for prostate cancer. However, the mechanisms underlying the development of radiation resistance in prostate cancer remain unclear. The glucose metabolism is critical in cancer radioresistance. Our proteomics results showed that glycolysis is involved in prostate cancer radioresistance. We found that the expression of ALDOA gene was up-regulated in prostate cancer radioresistance. Inhibition of ALDOA expression increases radiosensitivity in prostate cancer. The results suggest that ALDOA plays an important role in radioresistance of prostate cancer. Therefore, we hypothesise that ALDOA may improve the radiosensitivity of prostate cancer by regulating the glycolysis pathway. The objectives of this project is to investigate the role of ALDOA in prostate cancer radioresistance using in vitro cell lines, in vivo animal models as well as human tissue samples; to explore the effect of ALDOA on prostate cancer radiosensitivity; to investigate the mechanism of ALDOA in prostate cancer radioresistance via regulating the glycolysis pathway. The study will provide an important theoretical base for exploring the mechanism of ALDOA in prostate cancer radioresistance and new therapeutic targets for prostate cancer radiotherapy. The findings from this project may have clinical significance for the recurrent prostate cancer patients after radiotherapy.

放疗抵抗是前列腺癌放疗后发现局部复发或转移的主要原因之一，但前列腺癌放疗抵抗的发生发展机制尚不清楚。研究表明糖代谢在肿瘤放疗抵抗发生发展中十分重要，我们前期蛋白组学研究发现糖酵解参与前列腺癌放疗抵抗，糖酵解途径关键基因醛缩酶A(ALDOA)在前列腺癌放疗抵抗中表达上调，同时抑制ALDOA表达能增加前列腺癌放疗敏感性,提示ALDOA在前列腺癌放疗抵抗中起重要作用,我们提出假说：ALDOA通过调控糖酵解通路影响前列腺放疗抵抗的作用，进而提高放疗敏感性。本课题拟从细胞、动物以及人类标本等多层次明确ALDOA在前列腺癌放疗抵抗中的作用；探讨ALDOA对前列腺癌放疗敏感性的影响；揭示ALDOA通过调控糖酵解通路影响前列腺放疗抵抗的作用机制。本研究为探讨ALDOA在前列腺放疗抵抗的发生机制提供重要的理论基础，为前列腺癌放疗增敏提供新靶点和新思路，对前列腺癌放疗后复发的病人具有重要临床意义。

放疗抵抗是前列腺癌放疗后发现局部复发或转移的主要原因之一，但前列腺癌放疗抵抗的发生发展机制尚不清楚。研究表明糖代谢在肿瘤放疗抵抗发生发展中十分重要，我们前期蛋白组学研究发现糖酵解参与前列腺癌放疗抵抗，糖酵解途径关键基因醛缩酶A(ALDOA)在前列腺癌放疗抵抗中表达上调，同时抑制ALDOA表达能增加前列腺癌放疗敏感性,提示ALDOA在前列腺癌放疗抵抗中起重要作用,我们提出假说：ALDOA通过调控糖酵解通路影响前列腺放疗抵抗的作用，进而提高放疗敏感性。本课题从细胞、动物以及人类标本等多层次明确ALDOA在前列腺癌放疗抵抗中的作用；探讨ALDOA对前列腺癌放疗敏感性的影响；揭示ALDOA通过调控糖酵解通路影响前列腺放疗抵抗的作用机制。同时我们发现PI3K/mTOR双抑制剂BEZ235在与癌症干细胞消退相关的前列腺癌辐射抗性动物模型中增强放射治疗敏感性。本研究为探讨ALDOA在前列腺放疗抵抗的发生机制提供重要的理论基础，为前列腺癌放疗增敏提供新靶点和新思路，对前列腺癌放疗后复发的病人具有重要临床意义。