二甲双胍靶向 c-MYC 癌基因预防前列腺癌。
Metformin targets c-MYC oncogene to prevent prostate cancer.
机构信息
Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY 10010-4086, USA.
出版信息
Carcinogenesis. 2013 Dec;34(12):2823-32. doi: 10.1093/carcin/bgt307. Epub 2013 Oct 15.
UNLABELLED
Prostate cancer (PCa) is the second leading cause of cancer-related death in American men and many PCa patients develop skeletal metastasis. Current treatment modalities for metastatic PCa are mostly palliative with poor prognosis. Epidemiological studies indicated that patients receiving the diabetic drug metformin have lower PCa risk and better prognosis, suggesting that metformin may have antineoplastic effects. The mechanism by which metformin acts as chemopreventive agent to impede PCa initiation and progression is unknown. The amplification of c-MYC oncogene plays a key role in early prostate epithelia cell transformation and PCa growth. The purpose of this study is to investigate the effect of metformin on c-myc expression and PCa progression. Our results demonstrated that (i) in Hi-Myc mice that display murine prostate neoplasia and highly resemble the progression of human prostate tumors, metformin attenuated the development of prostate intraepithelial neoplasia (PIN, the precancerous lesion of prostate) and PCa lesions. (ii) Metformin reduced c-myc protein levels in vivo and in vitro. In Myc-CaP mouse PCa cells, metformin decreased c-myc protein levels by at least 50%. (iii) Metformin selectively inhibited the growth of PCa cells by stimulating cell cycle arrest and apoptosis without affecting the growth of normal prostatic epithelial cells (RWPE-1). (iv) Reduced PIN formation by metformin was associated with reduced levels of androgen receptor and proliferation marker Ki-67 in Hi-Myc mouse prostate glands. Our novel findings suggest that by downregulating c-myc, metformin can act as a chemopreventive agent to restrict prostatic neoplasia initiation and transformation.
SUMMARY
Metformin, an old antidiabetes drug, may inhibit prostate intraepithelial neoplasia transforming to cancer lesion via reducing c-MYC, an 'old' overexpressed oncogene. This study explores chemopreventive efficacy of metformin in prostate cancer and its link to cMYC in vitro and in vivo.
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前列腺癌（PCa）是美国男性癌症相关死亡的第二大原因，许多 PCa 患者会发生骨转移。目前转移性 PCa 的治疗方法主要是姑息性的，预后较差。流行病学研究表明，接受糖尿病药物二甲双胍治疗的患者患 PCa 的风险较低，预后较好，这表明二甲双胍可能具有抗肿瘤作用。二甲双胍作为化学预防剂作用于阻止 PCa 起始和进展的机制尚不清楚。c-MYC 癌基因的扩增在早期前列腺上皮细胞转化和 PCa 生长中起着关键作用。本研究旨在研究二甲双胍对 c-myc 表达和 PCa 进展的影响。我们的结果表明：（i）在 Hi-Myc 小鼠中，其显示出鼠类前列腺肿瘤，并高度类似于人类前列腺肿瘤的进展，二甲双胍减弱了前列腺上皮内瘤变（PIN，前列腺的癌前病变）和 PCa 病变的发展。（ii）二甲双胍在体内和体外均降低了 c-myc 蛋白水平。在 Myc-CaP 小鼠 PCa 细胞中，二甲双胍至少降低了 50%的 c-myc 蛋白水平。（iii）二甲双胍通过刺激细胞周期停滞和细胞凋亡选择性地抑制 PCa 细胞的生长，而不影响正常前列腺上皮细胞（RWPE-1）的生长。（iv）二甲双胍减少 PIN 的形成与 Hi-Myc 小鼠前列腺中雄激素受体和增殖标志物 Ki-67 水平降低有关。我们的新发现表明，通过下调 c-myc，二甲双胍可以作为一种化学预防剂，限制前列腺肿瘤的起始和转化。
摘要
二甲双胍是一种古老的抗糖尿病药物，通过降低 c-MYC（一种过度表达的“老”癌基因），可能抑制前列腺上皮内瘤变转化为癌症病变。本研究探讨了二甲双胍在前列腺癌中的化学预防效果及其与 cMYC 在体外和体内的关系。
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