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首页> 外文期刊>Endocrine Connections >Insulin receptor compensates for IGF1R inhibition and directly induces mitogenic activity in prostate cancer cells
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Insulin receptor compensates for IGF1R inhibition and directly induces mitogenic activity in prostate cancer cells

机译：胰岛素受体补偿IGF1R抑制并直接诱导前列腺癌细胞的促有丝分裂活性

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Hyperinsulinemia is a major complication associated with the development of insulin resistance. In addition to its normal spectrum of metabolic effects, insulin can act as a growth factor and has the ability to promote mitogenic activity. Thus, hyperinsulinemia is regarded as a potentially important cancer risk factor among diabetic patients. However, the mechanisms of action of insulin in the specific context of prostate cancer (PCa) and, in particular, the specific receptor that mediates its actions have not been elucidated yet. The aims of this study were to investigate whether insulin can directly induce mitogenic activities in PCa-derived cell lines and to examine the mechanisms responsible for these actions. To this end, we used several PCa-derived cell lines, representing early and advanced stages of the disease. Our results indicated that insulin induces cell proliferation in a dose-dependent fashion in the LNCaP, C4-2, and P69 cell lines. We also demonstrated that insulin enabled LNCaP and C4-2 cells to progress through the cell cycle. Immunoprecipitation assays revealed that insulin activated the insulin receptor (INSR), but not the IGF1 receptor (IGF1R). In addition, INSR was able to compensate for and mediate IGF1 mitogenic signals following IGF1R inhibition. In conclusion, insulin exhibits direct mitogenic activities in PCa cells, which are mediated exclusively through the INSR. Further research is needed to fully dissect the molecular mechanisms underlying the biological actions of insulin in PCa. Keywords: insulin, insulin receptor, insulin-like growth factor-1 (IGF1), IGF1 receptor, prostate cancerIntroductionProstate cancer (PCa) is the second most frequently diagnosed cancer in men and the third most common cause of death in men aged over 50 years in developed countries. Apart from age, race, and a positive family history are among the strongest known risk factors for the disease (1). The incidence of PCa has substantially increased in the past two decades, making it one of the most severe public health threats in current medicine. PCa, if diagnosed during its early stages, can be cured surgically or by radiotherapy. However, few therapeutic choices are available for patients with metastatic disease and those with castration-resistant PCa (2). Therefore, developing new treatment options to treat these aggressive forms of PCa has a very high priority. Novel agents targeting pathways involved in proliferation, apoptosis, or immune modulation have entered clinical trials (3). For example, epidermal growth factor receptor tyrosine kinase and vascular endothelial growth factor inhibitors are effectively used in clinical settings (2, 4).The insulin-like growth factor (IGF) system has an important role in the normal growth and development of the prostate gland (5). In addition to its physiological role, epidemiological, clinical, and experimental evidence suggests an association between IGF system components and PCa development (1). In particular, a close functional connection has been identified between the IGF1 receptor (IGF1R), a transmembrane heterotetramer primarily involved in the mediation of IGF1 signals, and the androgen receptor (AR), a key element in prostate gland function. In recent years, the IGF1R has emerged as a promising therapeutic target in cancers, including prostate tumors.The clinical and metabolic importance of insulin has been well established (6, 7). In addition to its key role in the maintenance of glucose homeostasis (8), insulin and its receptor (INSR) are involved in the development of a number of metabolic conditions, including obesity and type 2 diabetes (9). The fact that these diseases are regarded as risk factors for cancer raises the question whether there is a direct connection between insulin and INSR and cancer. Elevated levels of insulin and INSR have been reported in several human cancers, including breast, colon, and lung, suggesting the existence of a common etiological link. However, the mechanisms of action of insulin in the specific context of PCa and, in particular, the specific receptor that mediates its actions have not been elucidated yet.The INSR shares a high structural homology with the IGF1R (84% similarity in the tyrosine kinase domain, 45–65% in the ligand-binding domain, and more than 50% in the overall amino acid sequence). In addition, ligand-dependent activation of the INSR and IGF1R activates almost identical downstream signaling cascades (10). However, whereas the IGF1R has been identified as a potential therapeutic target in cancer, such a validation is still lacking for the closely related INSR. The aims of the present study were to examine the hypothesis that insulin can directly induce mitogenic activity in PCa cells via its cognate receptor and to investigate the ability of INSR to compensate for and mediate IGF1 mitogenic signals following IGF1R inhibition.Subjects and methodsCell lines and treatmentsThe P69 and M12 PCa cell lin
机译：高胰岛素血症是与胰岛素抵抗发展有关的主要并发症。除了正常的代谢作用谱外，胰岛素还可以充当生长因子并具有促进促有丝分裂活性的能力。因此，高胰岛素血症被认为是糖尿病患者中潜在的重要癌症危险因素。然而，尚未阐明胰岛素在前列腺癌（PCa）的特定情况下的作用机制，尤其是介导其作用的特定受体。这项研究的目的是调查胰岛素是否可以直接诱导PCa衍生细胞系中的促有丝分裂活性，并研究引起这些作用的机制。为此，我们使用了几种PCa衍生的细胞系，分别代表该疾病的早期和晚期。我们的结果表明，胰岛素在LNCaP，C4-2和P69细胞系中以剂量依赖性方式诱导细胞增殖。我们还证明了胰岛素使LNCaP和C4-2细胞能够在整个细胞周期中发展。免疫沉淀测定表明，胰岛素激活了胰岛素受体（INSR），但没有激活IGF1受体（IGF1R）。此外，在IGF1R抑制后，INSR能够补偿和介导IGF1有丝分裂信号。总之，胰岛素在PCa细胞中表现出直接的促有丝分裂活性，仅通过INSR介导。需要进一步研究以充分剖析PCa中胰岛素的生物学作用的分子机制。关键字：胰岛素，胰岛素受体，胰岛素样生长因子1（IGF1），IGF1受体，前列腺癌简介前列腺癌（PCa）是男性中第二大最常被诊断出的癌症，也是50岁以上男性中第三大最常见的死因在发达国家。除年龄外，种族和阳性家族史是已知的最强疾病危险因素之一（1）。在过去的二十年中，PCa的发病率大大增加，使其成为当前医学中最严重的公共卫生威胁之一。如果PCa早期诊断出来，则可以通过手术或放射疗法治愈。但是，对于转移性疾病患者和去势抵抗性PCa的患者，几乎没有治疗选择（2）。因此，开发新的治疗方法来治疗这些侵袭性PCa具有很高的优先级。针对与增殖，凋亡或免疫调节有关的途径的新型药物已进入临床试验（3）。例如，表皮生长因子受体酪氨酸激酶和血管内皮生长因子抑制剂可在临床环境中有效使用（2，4）。胰岛素样生长因子（IGF）系统在前列腺的正常生长和发育中起重要作用腺体（5）。除了其生理作用外，流行病学，临床和实验证据还表明，IGF系统组成与PCa的发育之间存在关联（1）。特别是，在主要参与IGF1信号介导的跨膜异四聚体IGF1受体（IGF1R）与前列腺素功能中的关键要素雄激素受体（AR）之间已发现紧密的功能连接。近年来，IGF1R已成为包括前列腺肿瘤在内的多种癌症的理想治疗靶点。胰岛素的临床和代谢重要性已得到公认（6，7）。胰岛素及其受体（INSR）除了在维持葡萄糖体内稳态中起关键作用外（8），还参与了许多代谢疾病的发展，包括肥胖症和2型糖尿病（9）。这些疾病被视为癌症的危险因素这一事实提出了一个问题，即胰岛素与INSR和癌症之间是否存在直接联系。在几种人类癌症（包括乳腺癌，结肠癌和肺癌）中，胰岛素和INSR的水平已有报道，这表明存在共同的病因。然而，尚未阐明胰岛素在PCa特定环境中的作用机制，特别是在其介导其作用的特定受体方面的作用机制.INSR与IGF1R具有高度的结构同源性（酪氨酸激酶的相似性为84％ （在配体结合结构域中占45–65％，在整个氨基酸序列中超过50％）。此外，INSR和IGF1R的配体依赖性激活可激活几乎相同的下游信号传导级联（10）。但是，尽管已将IGF1R确定为癌症的潜在治疗靶标，但对于紧密相关的INSR仍缺乏这种验证。本研究的目的是检验以下假设，即胰岛素可以通过其同源受体直接诱导PCa细胞的促有丝分裂活性，并研究INSR在IGF1R抑制后补偿和介导IGF1有丝分裂信号的能力。 P69和M12 PCa细胞林

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