Role of Akt/Protein Kinase B in Cancer Metastasis

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2023 Nov 25

PMID 38002001

Authors

Mohammad Islam

Sarah Jones

Ian Ellis

Affiliations

Soon will be listed here.

Abstract

Metastasis is a critical step in the process of carcinogenesis and a vast majority of cancer-related mortalities result from metastatic disease that is resistant to current therapies. Cell migration and invasion are the first steps of the metastasis process, which mainly occurs by two important biological mechanisms, i.e., cytoskeletal remodelling and epithelial to mesenchymal transition (EMT). Akt (also known as protein kinase B) is a central signalling molecule of the PI3K-Akt signalling pathway. Aberrant activation of this pathway has been identified in a wide range of cancers. Several studies have revealed that Akt actively engages with the migratory process in motile cells, including metastatic cancer cells. The downstream signalling mechanism of Akt in cell migration depends upon the tumour type, sites, and intracellular localisation of activated Akt. In this review, we focus on the role of Akt in the regulation of two events that control cell migration and invasion in various cancers including head and neck squamous cell carcinoma (HNSCC) and the status of PI3K-Akt pathway inhibitors in clinical trials in metastatic cancers.

Citing Articles

A dynamic co-expression approach reveals Gins2 as a potential upstream modulator of HNSCC metastasis.

Khayer N, Shabani S, Jalessi M, Joghataei M, Mahjoubi F Sci Rep. 2025; 15(1):3322.

PMID: 39865116 PMC: 11770085. DOI: 10.1038/s41598-024-82668-1.

Molecular pathways and targeted therapies in head and neck cancers pathogenesis.

Constantin M, Chifiriuc M, Bleotu C, Vrancianu C, Cristian R, Bertesteanu S Front Oncol. 2024; 14:1373821.

PMID: 38952548 PMC: 11215092. DOI: 10.3389/fonc.2024.1373821.

References

Bozulic L, Hemmings B . PIKKing on PKB: regulation of PKB activity by phosphorylation. Curr Opin Cell Biol. 2009; 21(2):256-61. DOI: 10.1016/j.ceb.2009.02.002. View

Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher A . Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999; 399(6736):601-5. DOI: 10.1038/21224. View

Bellacosa A, De Feo D, Godwin A, BELL D, Cheng J, Altomare D . Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer. 1995; 64(4):280-5. DOI: 10.1002/ijc.2910640412. View

Alessi D, Cohen P . Mechanism of activation and function of protein kinase B. Curr Opin Genet Dev. 1998; 8(1):55-62. DOI: 10.1016/s0959-437x(98)80062-2. View

Aceto N, Bardia A, Miyamoto D, Donaldson M, Wittner B, Spencer J . Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014; 158(5):1110-1122. PMC: 4149753. DOI: 10.1016/j.cell.2014.07.013. View

Larue L, Bellacosa A . Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene. 2005; 24(50):7443-54. DOI: 10.1038/sj.onc.1209091. View

Wu K, Fan J, Zhang L, Ning Z, Zeng J, Zhou J . PI3K/Akt to GSK3β/β-catenin signaling cascade coordinates cell colonization for bladder cancer bone metastasis through regulating ZEB1 transcription. Cell Signal. 2012; 24(12):2273-82. DOI: 10.1016/j.cellsig.2012.08.004. View

Liu P, Cheng H, Roberts T, Zhao J . Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009; 8(8):627-44. PMC: 3142564. DOI: 10.1038/nrd2926. View

Yokoyama K, Kimoto K, Itoh Y, Nakatsuka K, Matsuo N, Yoshioka H . The PI3K/Akt pathway mediates the expression of type I collagen induced by TGF-β2 in human retinal pigment epithelial cells. Graefes Arch Clin Exp Ophthalmol. 2011; 250(1):15-23. PMC: 3262137. DOI: 10.1007/s00417-011-1766-x. View

10.

Leber M, Efferth T . Molecular principles of cancer invasion and metastasis (review). Int J Oncol. 2009; 34(4):881-95. DOI: 10.3892/ijo_00000214. View

11.

Grille S, Bellacosa A, Upson J, Klein-Szanto A, van Roy F, Lee-Kwon W . The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res. 2003; 63(9):2172-8. View

12.

Liu L, Chen L, Luo Y, Chen W, Zhou H, Xu B . Rapamycin inhibits IGF-1 stimulated cell motility through PP2A pathway. PLoS One. 2010; 5(5):e10578. PMC: 2868031. DOI: 10.1371/journal.pone.0010578. View

13.

Denker S, Barber D . Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1. J Cell Biol. 2002; 159(6):1087-96. PMC: 2173980. DOI: 10.1083/jcb.200208050. View

14.

Miyazawa J, Mitoro A, Kawashiri S, Chada K, Imai K . Expression of mesenchyme-specific gene HMGA2 in squamous cell carcinomas of the oral cavity. Cancer Res. 2004; 64(6):2024-9. DOI: 10.1158/0008-5472.can-03-1855. View

15.

Feng Y, Walsh C . The many faces of filamin: a versatile molecular scaffold for cell motility and signalling. Nat Cell Biol. 2004; 6(11):1034-8. DOI: 10.1038/ncb1104-1034. View

16.

Stransky N, Egloff A, Tward A, Kostic A, Cibulskis K, Sivachenko A . The mutational landscape of head and neck squamous cell carcinoma. Science. 2011; 333(6046):1157-60. PMC: 3415217. DOI: 10.1126/science.1208130. View

17.

Yoeli-Lerner M, Toker A . Akt/PKB signaling in cancer: a function in cell motility and invasion. Cell Cycle. 2006; 5(6):603-5. DOI: 10.4161/cc.5.6.2561. View

18.

Yamamura Y, Asai N, Enomoto A, Kato T, Mii S, Kondo Y . Akt-Girdin signaling in cancer-associated fibroblasts contributes to tumor progression. Cancer Res. 2015; 75(5):813-23. DOI: 10.1158/0008-5472.CAN-14-1317. View

19.

Hart J, Vogt P . Phosphorylation of AKT: a mutational analysis. Oncotarget. 2011; 2(6):467-76. PMC: 3139455. DOI: 10.18632/oncotarget.293. View

20.

Wlodarski P, Grajkowska W, Lojek M, Rainko K, Jozwiak J . Activation of Akt and Erk pathways in medulloblastoma. Folia Neuropathol. 2006; 44(3):214-20. View