Cell survival and metastasis regulation by Akt signaling in colorectal cancer

Abstract

Dissemination of cancer cells to distant organ sites is the leading cause of death due to treatment failure in different types of cancer. Mehlen and Puisieux have reviewed the importance of the development of inappropriate cell survival signaling for various steps in the metastatic process and have noted the particular importance of aberrant cell survival to successful colonization at the metastatic site. Therefore, the understanding of mechanisms that govern cell survival fate of these metastatic cells could lead to the understanding of a new paradigm for the control of metastatic potential and could provide the basis for developing novel strategies for the treatment of metastases. Numerous studies have documented the widespread role of Akt in cell survival and metastasis in colorectal cancer, as well as many other types of cancer. Akt acts as a key signaling node that bridges the link between oncogenic receptors to many essential pro-survival cellular functions, and is perhaps the most commonly activated signaling pathway in human cancer. In recent years, Akt2 and Akt3 have emerged as significant contributors to malignancy alongside the well-characterized Akt1 isoform, with distinct non-overlapping functions. This review is aimed at gaining a better understanding of the Akt-driven cell survival mechanisms that contribute to cancer progression and metastasis and the pharmacological inhibitors in clinical trials designed to counter the Akt-driven cell survival responses in cancer.

Figure 1

PI3K/Akt signalling in cancer

Figure 2

Akt isoform functions in cancer

Figure 3

Predicted mRNA targets of Akt2 in context of colorectal cancer metastasis signalling

Figure 4

Loss of autocrine TGFβ leads to complex formation between Akt& Smad3 during stress (unpublished data)

Figure 5

TGFβ/PKA mediated Akt regulation leading to cell death in CRC