Role of adenosine A3 receptor in suppressing prostate cancer

描述（由申请人提供）：前列腺癌转移是前列腺癌的严重后遗症，与死亡率增加和治疗有效性降低相关。雄激素戒断疗法，治疗的标志促进肿瘤消退。然而，治疗效果在平均18-24个月后减弱，需要使用二线药物。化疗药物虽然有效，但不能治愈，因此迫切需要在疾病过程的早期开始新的治疗。我们的实验室最近表明，腺苷A3受体（A3 AR）亚型的激活抑制前列腺癌细胞增殖和转移的雄激素非依赖性转移性前列腺癌的大鼠和人类细胞系，并在SCID小鼠注射AT6.1大鼠转移性前列腺癌细胞系。“转移表型”部分地通过这些细胞经由NADPH氧化酶系统产生高水平的ROS来介导，NADPH氧化酶系统激活信号传导途径，例如核因子（NF）-：B和细胞外信号调节激酶（ERK）促分裂原活化蛋白（MAP）激酶/活化蛋白（AP-1）转录因子。通过这些机制，ROS积极调节与转移表型相关的蛋白质的表达。在这个提议中，我们将检验A3 AR的激活抑制NADPH氧化酶活性从而抑制下游信号通路的假设，主要是ERK 1/2 MAP激酶和NF-：B以及由ROS调节的转移基因表达。在严重联合免疫缺陷（SCID）小鼠模型中，我们将确定最佳的A3 AR治疗方案，以实现最大限度地抑制转移。具体目标是：（1）确定使用A3 AR激动剂减少前列腺癌转移的最佳治疗参数，重点是最佳剂量和治疗方案，并确定这些激动剂在建立细胞转移后是否有效。(2)确定A3 AR抑制ROS生成以及前列腺癌细胞运动和转移的机制。我们将重点关注NADPH氧化酶，并通过ERK 1/2 MAP激酶/AP-1和NF-：B途径确定其激活和亚基表达的机制。总之，这些研究将提供关于A3 AR激动剂在前列腺癌中的抗转移作用的疗效和机制的新信息，并为临床使用这类药物提供合理的依据。公共卫生相关性：前列腺癌转移是前列腺癌的严重后果，如果不及时治疗，可能导致死亡。有几种治疗方案，如雄激素戒断治疗和使用药物，如酮康唑和倍美力。此外，某些铂类抗癌剂也能有效对抗这种疾病，但会产生严重的副作用，如听力损失和肾衰竭。总的来说，这种治疗是没有治愈性的，迫切需要在疾病的早期进行新的治疗。我们已经证明，一种模拟体内内源性化学物质腺苷的化合物可以减少前列腺癌向肺的转移。然而，我们不知道这种有益的作用是如何产生的。此外，我们希望优化药物治疗，以减少肺转移。因此，这些目标将构成目前赠款提案的具体目标。我们相信，这项研究可能会发现一种新的治疗前列腺癌转移的方法。

DESCRIPTION (provided by applicant): Prostate cancer metastasis is a serious sequelae of prostate cancer, associated with increased mortality and reduces treatment effectiveness. Androgen withdrawal therapy, the hallmark of treatment promotes tumor regression. However, treatment benefits wane after an average of 18-24 months, necessitating the use of second-line agents. Chemotherapeutic agents though effective, are not curative and there is an urgent need for novel therapies to be initiated early in the course of the disease. Our laboratory has recently shown that activation of the adenosine A3 receptor (A3AR) subtype inhibits prostate cancer cell proliferation and metastasis in rat and human cell lines of androgen-independent metastatic prostate cancer and in SCID mice injected with the AT6.1 rat metastatic prostate cancer line. The "metastatic phenotype" is mediated in part through the generation of high levels of ROS by these cells via the NADPH oxidase system, which activates signaling pathways, such as nuclear factor (NF)-:B and extracellular signal regulated kinase (ERK) mitogen activated protein (MAP) kinase/activator protein (AP-1) transcription factor. Through these mechanisms, ROS positively regulates the expression of proteins linked to the metastatic phenotype. In this proposal, we will test the hypothesis that activation of the A3AR inhibits the NADPH oxidase activity and thereby suppresses downstream signaling pathways, primarily ERK1/2 MAP kinase and NF-:B and metastatic gene expression regulated by ROS. In a severe combined immunodeficient (SCID) mouse model, we will determine the optimal A3AR treatment protocol to effect maximum inhibition of metastasis. The specific goals are: (1) To determine the optimal treatment parameters for using A3AR agonist to reduce prostate cancer metastasis, focusing on optimal doses and treatment schedules and also determining whether these agonists are effective following establishment of cell metastasis. (2) To determine the mechanism(s) by which the A3AR inhibits ROS generation and motility and metastasis of prostate cancer cells. We will focus on NADPH oxidase and determine the mechanism(s) underlying its activation and subunit expression via the ERK1/2 MAP kinase/AP-1 and NF-:B pathways. Overall, these studies will provide novel information concerning the efficacy of and mechanism underlying the anti-metastatic actions of A3AR agonists in prostate cancer and provide a rational basis for using this class of drug clinically. PUBLIC HEALTH RELEVANCE: Prostate cancer metastasis is a serious consequence of prostate cancer, which if left untreated, could result in death. Several treatment options exist, such as androgen withdrawal therapy and the use of drugs such as ketoconazole and Premarin. In addition, certain platinum-based anti-cancer agents are also effective against the disease but do produce significant side effects such as hearing loss and kidney failure. Overall, such treatments are not curative and there is an urgent need for novel therapies early in the course of the disease. We have shown that a compound which mimics an endogenous chemical in the body, adenosine, can reduce the metastasis of prostate cancer to the lung. However, we do not know how this beneficial action is produced. In addition, we would like to optimize the drug treatment to produce more reductions in lung metastasis. Therefore, these goals will form the specific aims of the current grant proposal. We believe that this study could uncover a novel method of treating prostate cancer metastasis.