AKT Signaling and Its Consequences for Cancer

AKT signaling is crucial in cellular processes and often dysregulated in many cancers 1,2

PI3K/AKT/mTOR image: AKT serves as the central node of the pathway, regulating cell growth and proliferation

FOXO=Forkhead box O; GSK3=glycogen synthase kinase 3; mTORC=mammalian target of rapamycin complex; PDK1=phosphoinositide-dependent kinase-1; PI3K=phosphatidylinositol 3-kinase; PI4,5P2=phosphatidylinositol 4,5-bisphosphate; PIP3=phosphatidylinositol 3,4,5-trisphosphate; PTEN=phosphatase and tensin homolog; RTK=receptor tyrosine kinase.

AKT is the central node of the PI3K/AKT pathway and has an essential regulatory role in multiple cellular processes. 1-3 There are 3 highly homologous AKT isoforms (AKT 1, AKT 2, and AKT 3) that are encoded by separate genes and share over 80% amino acid sequence identity in mammalian cells. 4

AKT is one of the most frequently activated protein kinases in human cancers. Hyperactivation of AKT may induce cell growth, lead to cell proliferation, and contribute toward resistance to apoptosis. 3

In cancer, AKT activity is frequently elevated due to oncogenic growth factors, angiogenic factors, cytokines, and genetic alterations, including mutations and/or amplifications of the AKT1, AKT2, and AKT3 genes; loss of function of the phosphatase and tensin homolog (PTEN) tumor-suppressor; and mutations of the phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) gene.5,6 Inactivation of PTEN and missense alleles of PIK3CA have been associated with constitutive activation of AKT. AKT activation has been correlated with various clinicopathologic parameters such as advanced disease and/or poor prognosis in a number of tumors. 7

The oncogenic potential of the AKT pathway is further supported by the fact that a murine model-based conditional PTEN deletion, leading to increased activation of AKT signaling, may result in the development of metastatic cancer.8 Ectopic expression of constitutively active AKT resulted in oncogenic transformation, both in vitro and in vivo. In addition, downregulation or knockdown of AKT by antisense or small interfering ribonucleic acid (siRNA) significantly reduced tumor growth and invasiveness, as well as induced apoptosis and cell growth arrest only in tumor cells overexpressing AKT. 5

References

  1. Manning BD, Toker A. Cell. 2017;169:381-405. PMID: 28431241
  2. Testa JR, Tsichlis PN. Oncogene. 2005;24:7391-7393. PMID: 16288285
  3. Wan X, Harkavy B, Shen N, Grohar P, Helman LJ. Oncogene. 2007;26:1932-1940. PMID: 17001314
  4. Hay N. Cancer Cell. 2005;8:179-183. PMID: 16169463
  5. Cheng JQ, Lindsley CW, Cheng GZ, Yang H, Nicosia SV. Oncogene. 2005;24:7482-7492. PMID: 16288295
  6. Malanga D, Scrima M, De Marco C, et al. Cell Cycle. 2008;7:665-669. PMID: 18256540
  7. Altomare DA, Testa JR. Oncogene. 2005;24:7455-7464. PMID: 16288292
  8. Statz CM, Patterson SE, Mockus SM. Targ Oncol. 2017;12:47-59. PMID: 27503005