Lysyl oxidase propeptide sensitizes pancreatic and breast cancer cells to doxorubicin-induced apoptosis.
Lysyl oxidase propeptide sensitizes pancreatic and breast cancer cells to doxorubicin-induced apoptosis.
复制标题
DOI：
10.1002/jcb.22828
复制
发表时间：
2010-12-01
影响因子：
4
通讯作者：
Kirsch, Kathrin H.
中科院分区：
文献类型：
--
作者：
Min, Chengyin;Zhao, Yingshe;Romagnoli, Mathilde;Trackman, Philip C.;Sonenshein, Gail E.;Kirsch, Kathrin H.
RAS突变或其上游受体酪氨酸激酶的激活通常与癌症对化疗的不良反应有关。从分泌的前体蛋白（Pro-LOX）释放的赖氨酰氧化酶（LOX-PP）的18 kDa前肽结构域已显示抑制RAS信号传导和培养物中乳腺癌、胰腺癌、肺癌和前列腺癌细胞的转化表型，以及小鼠异种移植模型中Her-2/neu驱动的乳腺癌细胞的肿瘤形成。在这里，我们测试了LOX-PP对由突变RAS驱动的MIA PaCa-2胰腺癌细胞的影响。在培养的MIA PaCa-2细胞中，LOX-PP减弱ERK和AKT活性，并降低NF-κB p65和RelB亚基以及细胞周期蛋白D1的水平，这些亚基由RAS信号转导激活。在小鼠异种移植物生长中，LOX-PP降低了这些胰腺癌细胞的肿瘤生长，以及p65 NF-κB亚基和细胞周期蛋白D1蛋白的核水平。虽然生物制剂在单独使用时减弱肿瘤生长，但当与化学治疗剂组合使用时，它们通常具有累加或协同效应。因此，我们接下来测试了LOX-PP使胰腺癌和乳腺癌细胞对化疗剂阿霉素敏感的假设。纯化的LOX-PP增强了阿霉素在胰腺癌和乳腺癌细胞中的细胞毒性作用，如通过ATP产生、细胞死亡ELISA测定、半胱天冬酶3活化、PARP切割和膜联蛋白V染色所判断的。因此，LOX-PP增强了多柔比星对乳腺癌和胰腺癌细胞的细胞毒性，从而使更多的研究与更广泛的当前癌症治疗方式相结合。
RAS mutations or its activation by upstream receptor tyrosine kinases are frequently associated with poor response of carcinomas to chemotherapy. The 18 kDa propeptide domain of lysyl oxidase (LOX-PP) released from the secreted precursor protein (Pro-LOX) has been shown to inhibit RAS signaling and the transformed phenotype of breast, pancreatic, lung, and prostate cancer cells in culture, and formation of tumors by Her-2/neu-driven breast cancer cells in a mouse xenograft model. Here, we tested the effects of LOX-PP on MIA PaCa-2 pancreatic cancer cells, driven by mutant RAS. In MIA PaCa-2 cells in culture, LOX-PP attenuated the ERK and AKT activities and decreased the levels of the NF-κB p65 and RelB subunits and cyclin D1, which are activated by RAS signaling. In mouse xenograft growth, LOX-PP reduced growth of tumors by these pancreatic cancer cells, and the nuclear levels of the p65 NF-κB subunit and cyclin D1 proteins. While biological agents attenuate tumor growth when used alone, often they have additive or synergistic effects when used in combination with chemotherapeutic agents. Thus, we next tested the hypotheses that LOX-PP sensitizes pancreatic and breast cancer cells to the chemotherapeutic agent doxorubicin. Purified LOX-PP enhanced the cytotoxic effects of doxorubicin in pancreatic and breast cancer cells, as judged by ATP production, Cell Death ELISA assays, caspase 3 activation, PARP cleavage, and Annexin V staining. Thus, LOX-PP potentiates the cytotoxicity of doxorubicin on breast and pancreatic cancer cells, warranting additional studies with a broader spectrum of current cancer treatment modalities.
登录
查看更多内容
影响因子：
8
作者：
Patel, NM;Nozaki, S;Nakshatri, H
通讯作者：
Nakshatri, H
影响因子：
11.2
作者：
Wu, Min;Min, Chengyin;Sonenshein, Gail E.
通讯作者：
Sonenshein, Gail E.
影响因子：
4.8
作者：
Kirsch, KH;Georgescu, MM;Hanafusa, H
通讯作者：
Hanafusa, H
影响因子：
11.2
作者：
Nahta, R;Hung, MC;Esteva, FJ
通讯作者：
Esteva, FJ
影响因子：
11.2
作者：
Min, Chengyin;Kirsch, Kathrin H.;Sonenshein, Gail E.
通讯作者：
Sonenshein, Gail E.