Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
Mol Cancer Ther. 2018 Sep;17(9):1951-1960. doi: 10.1158/1535-7163.MCT-17-1002. Epub 2018 Jun 22.
Prostate cancer is a principal cause of cancer-associated morbidity in men. Although 5-year survival of patients with localized prostate cancer approaches 100%, survival decreases precipitously after metastasis. Bone is the preferred site for disseminated prostate cancer cell colonization, altering the equilibrium of bone homeostasis resulting in weak and fragile bones. Currently, no curative options are available for prostate cancer bone metastasis. Melanoma differentiation associated gene-7 (MDA-7)/IL24 is a well-studied cytokine established as a therapeutic in a wide array of cancers upon delivery as a gene therapy. In this study, we explored the potential anticancer properties of MDA-7/IL24 delivered as a recombinant protein. Using bone metastasis experimental models, animals treated with recombinant MDA-7/IL24 had significantly less metastatic lesions in their femurs as compared with controls. The inhibitory effects of MDA-7/IL24 on bone metastasis resulted from prostate cancer-selective killing and inhibition of osteoclast differentiation, which is necessary for bone resorption. Gain- and loss-of-function genetic approaches document that prosurvival Akt and Mcl-1 pathways are critically important in the antibone metastatic activity of MDA-7/IL24. Our previous findings showed that MDA-7/IL24 gene therapy plus Mcl-1 inhibitors cooperate synergistically. Similarly, an Mcl-1 small-molecule inhibitor synergized with MDA-7/IL24 and induced robust antibone metastatic activity. These results expand the potential applications of MDA-7/IL24 as an anticancer molecule and demonstrate that purified recombinant protein is nontoxic in preclinical animal models and has profound inhibitory effects on bone metastasis, which can be enhanced further when combined with an Mcl-1 inhibitory small molecule. .
前列腺癌是导致男性癌症相关发病率的主要原因。虽然局限性前列腺癌患者的 5 年生存率接近 100%，但转移后生存率急剧下降。骨骼是转移性前列腺癌细胞定植的首选部位，改变了骨内稳态的平衡，导致骨骼脆弱。目前，对于前列腺癌骨转移还没有治愈的选择。黑色素瘤分化相关基因-7（MDA-7）/白细胞介素 24（IL24）是一种经过广泛研究的细胞因子，作为一种基因治疗药物，在多种癌症中被证实具有治疗作用。在这项研究中，我们探索了作为重组蛋白传递的 MDA-7/IL24 的潜在抗癌特性。使用骨转移实验模型，与对照组相比，用重组 MDA-7/IL24 治疗的动物其股骨中的转移病灶明显减少。MDA-7/IL24 对骨转移的抑制作用源于对前列腺癌细胞的选择性杀伤和破骨细胞分化的抑制，破骨细胞分化是骨吸收所必需的。获得和丧失功能的遗传方法表明，生存的 Akt 和 Mcl-1 途径在 MDA-7/IL24 的抗骨转移活性中至关重要。我们之前的研究结果表明，MDA-7/IL24 基因治疗加 Mcl-1 抑制剂协同作用。同样，Mcl-1 小分子抑制剂与 MDA-7/IL24 协同作用，诱导强烈的抗骨转移活性。这些结果扩展了 MDA-7/IL24 作为抗癌分子的潜在应用，并证明纯化的重组蛋白在临床前动物模型中是无毒的，对骨转移具有显著的抑制作用，当与 Mcl-1 抑制性小分子联合使用时，这种抑制作用可以进一步增强。
