Razidlo Gina L, Magnine Christopher, Sletten Arthur C, Hurley Rachel M, Almada Luciana L, Fernandez-Zapico Martin E, Ji Baoan, McNiven Mark A
Center for Basic Research in Digestive Diseases, Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
Center for Basic Research in Digestive Diseases, Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota.
Cancer Res. 2015 Jul 15;75(14):2907-15. doi: 10.1158/0008-5472.CAN-14-3103. Epub 2015 May 14.
Pancreatic cancer, one of the most lethal forms of human cancer, is largely resistant to many conventional chemotherapeutic agents. Although many therapeutic approaches focus on tumor growth, metastasis is a primary factor contributing to lethality. Therefore, novel therapies to target metastatic invasion could prevent tumor spread and recurrence resulting from local and distant metastasis. The protein Vav1 is aberrantly expressed in more than half of pancreatic cancers. Its expression promotes activation of Rac and Cdc42 and leads to enhanced invasion and migration, as well as increased tumor cell survival and proliferation, suggesting that Vav1 could be a potent therapeutic target for pancreatic cancer. The purine analogue azathioprine, well known for its function as an anti-inflammatory compound, was recently shown to function by inhibiting Vav1 signaling in immune cells. We therefore hypothesized that azathioprine could also inhibit Vav1 in pancreatic tumor cells to reduce its proinvasive functions. Indeed, we have found that treatment of cultured pancreatic tumor cells with azathioprine inhibited Vav1-dependent invasive cell migration and matrix degradation, through inhibition of Rac and Cdc42 signaling. Furthermore, azathioprine treatment decreased metastasis in both xenograft and genetic mouse models of pancreatic cancer. Strikingly, metastasis was dramatically reduced in Vav1-expressing tumors arising from p48(Cre/+), Kras(G12D/+), p53(F/+) mice. These inhibitory effects were mediated through Vav1, as Vav1-negative cell lines and tumors were largely resistant to azathioprine treatment. These findings demonstrate that azathioprine and related compounds could be potent antimetastatic agents for Vav1-positive pancreatic tumors.
胰腺癌是人类癌症中最致命的形式之一，对许多传统化疗药物具有很大的抗性。尽管许多治疗方法都集中在肿瘤生长上，但转移是导致致死率的主要因素。因此，针对转移性侵袭的新型疗法可以预防由局部和远处转移引起的肿瘤扩散和复发。蛋白质Vav1在超过一半的胰腺癌中异常表达。它的表达促进Rac和Cdc42的激活，并导致侵袭和迁移增强，以及肿瘤细胞存活和增殖增加，这表明Vav1可能是胰腺癌的一个有效治疗靶点。嘌呤类似物硫唑嘌呤以其作为抗炎化合物的功能而闻名，最近被证明在免疫细胞中通过抑制Vav1信号发挥作用。因此，我们假设硫唑嘌呤也可以抑制胰腺肿瘤细胞中的Vav1，以降低其促侵袭功能。事实上，我们发现用硫唑嘌呤处理培养的胰腺肿瘤细胞可通过抑制Rac和Cdc42信号来抑制Vav1依赖性侵袭性细胞迁移和基质降解。此外，硫唑嘌呤处理可降低胰腺癌异种移植模型和基因小鼠模型中的转移。引人注目的是，在由p⁴⁸(Cre/+), Kras(G12D/+), p⁵³(F/+)小鼠产生的表达Vav1的肿瘤中，转移显著减少。这些抑制作用是通过Vav1介导的，因为Vav1阴性细胞系和肿瘤对硫唑嘌呤处理基本具有抗性。这些发现表明，硫唑嘌呤及相关化合物可能是Vav1阳性胰腺肿瘤的有效抗转移剂。
