Identification of a novel TGFβ/PKA signaling transduceome in mediating control of cell survival and metastasis in colon cancer.
Identification of a novel TGFβ/PKA signaling transduceome in mediating control of cell survival and metastasis in colon cancer.
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DOI：
10.1371/journal.pone.0019335
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发表时间：
2011-05-03
期刊：
影响因子：
3.7
通讯作者：
Brattain MG
中科院分区：
文献类型：
--
作者：
Chowdhury S;Howell GM;Rajput A;Teggart CA;Brattain LE;Weber HR;Chowdhury A;Brattain MG
了解人类癌症转移的驱动因素对于开发治疗转移的潜在疗法非常重要。tgf - β肿瘤抑制活性的丧失在转移过程中的作用基本上是未知的。利用体外和体内技术，我们已经证明tgf - β肿瘤抑制信号的丢失对于转移过程的最后一步-转移部位的定植是必要的。这项工作首次证明了TGFβ受体重组导致转移性定植减少。此外，我们已经确定了一种新的TGFβ/PKA肿瘤抑制途径，该途径直接作用于已知的细胞存活机制，该机制通过survivin/XIAP依赖性抑制影响细胞凋亡的caspases来响应应激。tgf - β/PKA信号转导组通过诱导细胞死亡与转移控制之间的联系被证明是通过在受体缺乏的转移性结肠癌细胞中恢复tgf - β受体和重新激活tgf - β/PKA通路导致异常细胞存活的控制。这项工作影响了我们对转移瘤生长和维持的可能机制的理解，以及对TGFβ作为转移抑制因子的新功能的理解。这些结果提出了一种可能性，即减弱的tgf - β信号的再生可能是治疗转移的有效靶点。我们的工作表明，通过多方面的TGFβ/PKA转导组诱导途径抑制这种非常重要的异常细胞存活机制，开发抗转移治疗的临床潜力。由于转移性肿瘤是实体瘤死亡的主要原因，因此迫切需要开发有效的转移性疾病治疗方法。
Understanding drivers for metastasis in human cancer is important for potential development of therapies to treat metastases. The role of loss of TGFβ tumor suppressor activities in the metastatic process is essentially unknown. Utilizing in vitro and in vivo techniques, we have shown that loss of TGFβ tumor suppressor signaling is necessary to allow the last step of the metastatic process - colonization of the metastatic site. This work demonstrates for the first time that TGFβ receptor reconstitution leads to decreased metastatic colonization. Moreover, we have identified a novel TGFβ/PKA tumor suppressor pathway that acts directly on a known cell survival mechanism that responds to stress with the survivin/XIAP dependent inhibition of caspases that effect apoptosis. The linkage between the TGFβ/PKA transduceome signaling and control of metastasis through induction of cell death was shown by TGFβ receptor restoration with reactivation of the TGFβ/PKA pathway in receptor deficient metastatic colon cancer cells leading to control of aberrant cell survival. This work impacts our understanding of the possible mechanisms that are critical to the growth and maintenance of metastases as well as understanding of a novel TGFβ function as a metastatic suppressor. These results raise the possibility that regeneration of attenuated TGFβ signaling would be an effective target in the treatment of metastasis. Our work indicates the clinical potential for developing anti-metastasis therapy based on inhibition of this very important aberrant cell survival mechanism by the multifaceted TGFβ/PKA transduceome induced pathway. Development of effective treatments for metastatic disease is a pressing need since metastases are the major cause of death in solid tumors.
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