Effects of tumor-suppressor lysyl oxidase propeptide on prostate cancer xenograft growth and its direct interactions with DNA repair pathways.
Effects of tumor-suppressor lysyl oxidase propeptide on prostate cancer xenograft growth and its direct interactions with DNA repair pathways.
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作者：
赖氨酰氧化酶（LOX）是正常胶原蛋白和弹性蛋白生物合成和成熟所需的多功能蛋白质。此外，LOX在癌症中具有复杂的作用，其中分泌的pro-LOX的赖氨酰氧化酶前肽（LOX-PP）结构域具有肿瘤抑制活性，而活性酶促进转移。在前列腺癌细胞系中，重组LOX-PP（rLOX-PP）通过尚未表征的机制抑制体外PC 3细胞的生长，而在DU 145细胞中，rLOX-PP靶向FGF信号传导。因为rLOX-PP可以增强基因毒性化疗剂对乳腺癌细胞凋亡的作用，我们推断rLOX-PP可以靶向癌症中通常升高的DNA修复途径。在这里，我们首次证明，rLOX-PP抑制前列腺异种移植物在体内的生长和激活的关键DNA修复分子ATM和CHK 2的磷酸化抑制rLOX-PP在体内的表达。此外，体外研究表明，rLOX-PP抑制辐射诱导的ATM和CHK 2的活化磷酸化，并且外源添加的rLOX-PP蛋白可以定位于DU 145和PC 3细胞的细胞核。rLOX-PP下拉研究导致在两种细胞系中检测到与核DNA修复调节剂MRE 11的蛋白复合物，并且rLOX-PP定位于辐射诱导的核DNA修复灶。最后，rLOX-PP显示出使DU 145和PC 3细胞对在集落形成测定中确定的辐射诱导的细胞死亡敏感。这些数据提供了证据表明，rLOX-PP具有核作用机制，其中它直接与DNA修复蛋白相互作用，使前列腺癌细胞对电离辐射的作用敏感。
Lysyl oxidase (LOX) is a multifunctional protein required for normal collagen and elastin biosynthesis and maturation. In addition, LOX has complex roles in cancer in which the lysyl oxidase propeptide (LOX-PP) domain of secreted pro-LOX has tumor suppressor activity, while the active enzyme promotes metastasis. In prostate cancer cell lines, recombinant LOX-PP (rLOX-PP) inhibits the growth of PC3 cells in vitro by mechanisms which were not characterized, while in DU145 cells rLOX-PP targeted FGF signaling. Because rLOX-PP can enhance effects of a genotoxic chemotherapeutic on breast cancer cell apoptosis, we reasoned that rLOX-PP could target DNA repair pathways typically elevated in cancer. Here we demonstrate for the first time that rLOX-PP inhibits prostate xenograft growth in vivo and that activating phosphorylations of the key DNA repair molecules ATM and CHK2 are inhibited by rLOX-PP expression in vivo. In addition, in vitro studies showed that rLOX-PP inhibits radiation induced activating phosphorylations of ATM and CHK2, and that exogenously added rLOX-PP protein can localize to the nucleus in both DU145 and PC3 cells. rLOX-PP pull-down studies resulted in detection of a protein complex with the nuclear DNA repair regulator MRE11 in both cell lines, and rLOX-PP localized to radiation-induced nuclear DNA repair foci. Finally, rLOX-PP was shown to sensitize both DU145 and PC3 cells to radiation-induced cell death determined in colony formation assays. These data provide evidence that rLOX-PP has a nuclear mechanism of action in which it directly interacts with DNA repair proteins to sensitize prostate cancer cells to the effects of ionizing radiation.
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影响因子：
3.7
作者：
Bais MV;Nugent MA;Stephens DN;Sume SS;Kirsch KH;Sonenshein GE;Trackman PC
通讯作者：
Trackman PC
影响因子：
64.5
作者：
Buis J;Wu Y;Deng Y;Leddon J;Westfield G;Eckersdorff M;Sekiguchi JM;Chang S;Ferguson DO
通讯作者：
Ferguson DO
影响因子：
4.1
作者：
Bais, M. V.;Wigner, N.;Young, M.;Toholka, R.;Graves, D. T.;Morgan, E. F.;Gerstenfeld, L. C.;Einhorn, T. A.
通讯作者：
Einhorn, T. A.
影响因子：
8
作者：
Kauffmann, A.;Rosselli, F.;Sarasin, A.
通讯作者：
Sarasin, A.
影响因子：
8
作者：
Delia, D;Fontanella, E;Mizutani, S
通讯作者：
Mizutani, S