Department of Neural & Behavioral Sciences, Penn State University College of Medicine, Hershey, PA 17033, USA.
Exp Biol Med (Maywood). 2013 Jun;238(6):589-99. doi: 10.1177/1535370213489492.
Triple negative breast cancer (TNBC) represents approximately 15% of the newly diagnosed cancers worldwide and is characterized by tissue lacking in estrogen, progesterone and human epidermal growth factor receptors. TNBC disproportionately affects younger women and women of colour, and new treatments are needed. The opioid growth factor (OGF) - opioid growth factor receptor (OGFr) axis is a determinant of cell proliferation in neoplasia, and OGF is an endogenously produced pentapeptide that inhibits cell replication by interacting with OGFr and upregulating cyclin-dependent inhibitory kinase pathways thus reducing DNA synthesis. In these studies we investigated the presence and function of the OGF-OGFr axis in two human TNBC cell lines, as well as in breast cancer cell lines containing hormonal receptors. TNBC cell lines MDA-MD-231 and BT-20, as well as human breast cancer cells SK-BR-3 and MCF-7, were examined for the presence of pentapeptide and receptors, as well as their response to OGF. Specificity of peptide and receptor was confirmed by antibody neutralization and molecular studies to knockdown classical receptor protein. The requirement for protein transcription and translation and RNA transcription were investigated. Growth of TNBC cells in the presence of OGF and standard of care chemotherapeutic agent paclitaxel was evaluated to determine both efficacy and protective effects against toxicity. OGF treatment inhibited TNBC cells in a dosage related, receptor mediated, and reversible manner. OGF was the specific endogenous opioid to inhibit cell proliferation, and this was mediated by p21 cyclin dependent inhibitory kinase pathways, and required protein and RNA synthesis. OGFr was the specific receptor involved; both peptide and receptor were detected in all four cell lines. OGF treatment inhibited growth of all cancer cell lines evaluated, and reduced cell death in cultures exposed to paclitaxel. The OGF-OGFr axis is present and functioning in TNBC cell lines, and provides a novel biological pathway as potential therapy.
三阴性乳腺癌（TNBC）约占全球新诊断癌症的 15%，其特征是组织缺乏雌激素、孕激素和人表皮生长因子受体。TNBC 不成比例地影响年轻女性和有色人种女性，需要新的治疗方法。阿片样生长因子（OGF）-阿片样生长因子受体（OGFr）轴是肿瘤细胞增殖的决定因素，OGF 是一种内源性产生的五肽，通过与 OGFr 相互作用并上调细胞周期蛋白依赖性激酶途径来抑制细胞复制，从而减少 DNA 合成。在这些研究中，我们研究了两种人类 TNBC 细胞系以及含有激素受体的乳腺癌细胞系中 OGF-OGFr 轴的存在和功能。检查了 TNBC 细胞系 MDA-MD-231 和 BT-20 以及人乳腺癌细胞系 SK-BR-3 和 MCF-7 中五肽和受体的存在，以及它们对 OGF 的反应。通过抗体中和和分子研究来敲低经典受体蛋白，证实了肽和受体的特异性。研究了蛋白质转录和翻译以及 RNA 转录的需求。在 OGF 和标准护理化疗药物紫杉醇存在的情况下评估 TNBC 细胞的生长，以确定疗效和对毒性的保护作用。OGF 以剂量相关、受体介导和可逆转的方式抑制 TNBC 细胞。OGF 是特异性内源性阿片样物质，可抑制细胞增殖，这是通过 p21 细胞周期蛋白依赖性激酶途径介导的，需要蛋白质和 RNA 合成。OGFr 是涉及的特异性受体；四种细胞系中均检测到肽和受体。OGF 治疗抑制了所有评估的癌细胞系的生长，并减少了暴露于紫杉醇的培养物中的细胞死亡。OGF-OGFr 轴存在于 TNBC 细胞系中并发挥作用，为潜在治疗提供了新的生物学途径。
