Akt2 overexpression plays a critical role in the establishment of colorectal cancer metastasis
Akt2 overexpression plays a critical role in the establishment of colorectal cancer metastasis
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DOI：
10.1073/pnas.0810715105
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发表时间：
2008-12-23
影响因子：
11.1
通讯作者：
Evers, B. Mark
中科院分区：
文献类型：
--
作者：
Rychahou, Piotr G.;Kang, JungHee;Evers, B. Mark
结直肠癌是美国癌症相关死亡的第二大原因。了解不同的遗传和表观遗传变化有助于转移性病变的建立和发展是至关重要的新的治疗策略的发展。在寻找结直肠癌转移建立的关键调节因子时，我们发现丝氨酸/苏氨酸激酶Akt 2（一种已知的原癌基因）在晚期结直肠癌和转移性肿瘤中高度表达。在实验性肝转移模型中，抑制高转移性结直肠癌细胞中Akt 2的表达可抑制其转移能力。野生型Akt 1的过表达不能恢复Akt 2下调的细胞的转移潜能，因此提示单个Akt亚型的非冗余作用。相比之下，野生型表达PTEN的SW 480结直肠癌细胞中Akt 2过表达导致微转移的形成;然而，持续形成明显的转移需要PTEN的缺失。最后，我们发现，PTEN丢失和Akt 2过表达的结果协同作用，以促进转移。这些结果支持Akt 2过表达在转移性结直肠癌中的作用，并建立了Akt 2过表达和转移性肿瘤建立和生长中的PTEN突变之间的机制联系。总之，这些数据表明Akt家族成员在肿瘤进展中具有不同的功能作用，并且选择性靶向PI 3 K/Akt 2通路可能为结直肠癌转移提供新的治疗策略。
Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Understanding the distinct genetic and epigenetic changes contributing to the establishment and growth of metastatic lesions is crucial for the development of novel therapeutic strategies. In a search for key regulators of colorectal cancer metastasis establishment, we have found that the serine/threonine kinase Akt2, a known proto-oncogene, is highly expressed in late-stage colorectal cancer and metastatic tumors. Suppression of Akt2 expression in highly metastatic colorectal carcinoma cells inhibits their ability to metastasize in an experimental liver metastasis model. Overexpression of wild-type Akt1 did not restore metastatic potential in cells with downregulated Akt2, thus suggesting non-redundant roles for the individual Akt isoforms. In contrast, Akt2 overexpression in wild-type PTEN expressing SW480 colorectal cancer cells led to the formation of micrometastases; however, loss of PTEN is required for sustained formation of overt metastasis. Finally, we found that the consequence of PTEN loss and Akt2 overexpression function synergistically to promote metastasis. These results support a role for Akt2 overexpression in metastatic colorectal cancer and establish a mechanistic link between Akt2 overexpression and PTEN mutation in metastatic tumor establishment and growth. Taken together, these data suggest that Akt family members have distinct functional roles in tumor progression and that selective targeting of the PI3K/Akt2 pathway may provide a novel treatment strategy for colorectal cancer metastasis.