FOXO3a-活性氧信号通路在前列腺癌发生发展和治疗中的作用研究

Accumulating evidence shows that oxidative stress is implicated in the progression of prostate cancer. Forkhead box O3A (FOXO3a) is a central protein that regulates the oxidative status in cells. Our previous study showed that androgen treatment suppressed the transcriptional activity of FOXO3a, hampered the expression of catalase antioxidase and increased reactive oxygen species (ROS), which in turn led to accelerated cell proliferation and enhanced cell invasion. Furthermore, compare to androgen-dependent prostate cancer LNCaP cell line, androgen-independent PC-3 cell line displays more depressed FOXO3a activity and catalase expression with higher ROS level. Therefore, it is very possible that FOXO3a-antioxidase-ROS pathway is involved in the formation of castration resistance. In this project, we will further elucidate the molecular mechanism of how androgen controls FOXO3a activity and confirm the key role of FOXO3a-andioxidase-ROS pathway in androgen-induced prostate cancer proliferation and metastasis. The pathological alteration of FOXO3a and its upstream/downstream molecules in castration-resistant prostate cancer will also be investigated. Finally, we will examine the antitumor effect of FOXO3a and antioxidants in androgen-independent prostate cancer. FOXO3a-ROS signaling pathway plays an important part in prostate cancer development. FOXO3a and ROS are promising candidate targets for prostate cancer therapy.

诸多证据表明，氧化应激参与前列腺癌的进展，抑癌基因FOXO3a是调控细胞氧化还原的关键分子。我们的前期研究发现，雄激素通过抑制FOXO3a的转录活性降低过氧化氢酶的表达，进而升高活性氧，促进癌细胞的增殖和转移。我们还发现，与雄激素依赖性前列腺癌LNCaP细胞相比，雄激素非依赖性PC-3细胞中，FOXO3a 的活性和过氧化氢酶的表达降低，活性氧升高，因此FOXO3a-抗氧化酶-活性氧通路很可能参与了前列腺癌去势抵抗的形成。在本研究中，我们将进一步阐明雄激素调控FOXO3a活性的机制，明确FOXO3a、抗氧化酶和活性氧在雄激素对前列腺癌的促进过程中是否发挥关键性作用，分析FOXO3a及其上下游分子在去势抵抗性前列腺癌中的病理变化，并探讨FOXO3a和抗氧化剂在前列腺癌治疗中的意义。FOXO3a-活性氧通路在前列腺癌的发生发展中发挥着重要作用，FOXO3a和活性氧可能成为前列腺癌治疗的潜在靶点。

氧化应激参与前列腺癌的进展，抑癌基因FOXO3a是调控细胞氧化还原的关键分子。我们的研究发现：（I）在雄激素依赖性前列腺癌LNCaP细胞中，双氢睾酮（Dihydrotestosterone，DHT）诱导细胞活性氧水平升高，（II）DHT对细胞ROS的调控作用是通过激活PI3K/Akt信号进而抑制FOXO3a/catalase通路实现的（图4）；（III）DHT对前列腺癌细胞增殖的刺激活性依赖其对细胞ROS的升高作用（IV）抗氧化剂处理能够抑制前列腺癌细胞的增殖；（V）在雄激素非依赖性前列腺癌LNCaP细胞中，FOXO3a/catalase的功能活性受到抑制，细胞ROS的水平升高。因此FOXO3a-抗氧化酶-活性氧通路很可能参与了前列腺癌去势抵抗的形成。本研究阐明了雄激素调控catalase活性的分子机制，明确了FOXO3a/catalase通路及细胞ROS在雄激素对前列腺癌的促进过程中发挥关键性作用。FOXO3a-活性氧通路在前列腺癌的发生发展中发挥着重要作用，FOXO3a和活性氧可能成为前列腺癌治疗的潜在靶点。