Table 1.
Function of Akt isoforms.
| Akt Isoform |
Cell line/Model System | Expression | Phenotype/Function | Potential Mechanisms | Ref |
|---|---|---|---|---|---|
| Akt2 | MDA-MB-231 | Akt2 siRNA | ↓ Cell proliferation, ↑ Mitophagy | ↓ Cyclin D1, ↑ p27, ↓ mTORC1, ↑ PGC-1⍺ | [71] |
| Akt1 | MDA-MB-231 | Akt1 siRNA | ↓ Cell proliferation, ↑ Apoptosis | ↓ Cyclin D1 | [72] |
| Akt2 | MDA-MB-231 | Akt2 nanobodies | ↓ Cell proliferation, ↑ Autophagy | ↓ Cyclin D1, ↑ LC3B-II | [73] |
| Akt1 | SKBR3 | Akt1 siRNA | ↓ Cell proliferation | ↑ p27 | [80] |
| Akt1 | MDA-MB-231 cell line & xenograft | Akt1 siRNA | ↓ Cell proliferation & tumor growth | [82] | |
| Akt2 | Akt2 siRNA | No effect on cell proliferation & tumor growth | |||
| Akt3 | Akt3 siRNA | ↓ Cell proliferation & tumor growth | |||
| Akt3 | Mouse mammary tumor C4 cells | Akt3 shRNA | ↓ Cell proliferation, ↑ Tamoxifen sensitivity | ↓ pErbB2/pErbB3, ↓ Foxo3a, ↑ ERα | [83] |
| Akt3 | MDA-MB-468 & MCF10DCIS xenografts | Akt3 shRNA | ↓ TNBC growth in 3D culture & xenografts | ↑ p27 | [63] |
| Akt3 | 3475 (metastatic MDA-MB-231 cell line) | Overexpression of Akt3/-S472 | ↓ Tumor growth & metastasis, ↑ Apoptosis | ↓ ERK, ↑ Bim, ↑ Bax activation | [84] |
| Akt1 | MDA-MB-231 | CA-Akt1 (Myr-Akt1) | ↓ Autophagy | ↓ UVRAG | [85] |
| Akt2 | CA-Akt2 (Myr-Akt2) | ↓ Autophagy | ↓ UVRAG | ||
| Akt2 | * MDA-MB-435 | WT Akt2 cDNA | ↑ Invasion & metastasis | ↑ β1-integrin | [86] |
| Akt1 | Transgenic mice with activated ErbB-2 | Activated Akt1 (Akt1-DD) | ↑ Cell proliferation, ↑ Tumorigenesis, ↓ Metastasis | ↑ Cyclin D1, ↑ Rb phosphorylation | [87] |
| Akt1 | Transgenic mice expressing | Activated Akt1 (Akt1-DD) | ↑ Tumorigenesis, ↓ Metastasis | ↑ Nuclear ER⍺ | [88] |
| Akt2 | ErbB2 or PyVmT | Activated Akt2 (Akt2-DD) | ↑ Invasion & metastasis | ||
| Akt1 | IGF-IR-overexpressing MCF-10A cell | Akt1 siRNA | ↓ Cell proliferation, ↑ EMT, ↑ Migration | ↑ ERK activity | [89] |
| Akt2 | monolayer and 3D culture | Akt2 siRNA | ↓ Cell proliferation, ↓ EMT, ↓ Migration | ||
| Akt1 | MDA-MB-231 | CA-Akt1 (Myr-Akt1) | ↓ Migration | ↑ Palladin phosphorylation (S507) | [90] |
| Akt1 | MDA-MB-231, * MDA-MB-435, SUM-159-PT | CA-Akt1 (Myr-Akt1) | ↓ Migration and invasion | ↑ HDM2 phosphorylation, ↓ NFAT1 | [91] |
| Akt1 | T4-2 cells and mouse xenografts | CA-Akt1 | ↑ Tumor growth, ↓ Cell migration & invasion | ↑ T1462 TSC2, ↓ TSC2, ↓ Rho-GTPase | [92] |
| Akt2 | MCF-7 and * MDA-MB-435 cells | Akt2 siRNA | ↓ Migration & invasion | Transactivation of Akt2 by Twist | [93] |
| Akt1 | IBH-6, T47D | shAkt1 | ↓ Tumor growth, ↑ Migration & invasion | ↓ Cyclin D1, ↑ β1-integrin & FAK | [70] |
| Akt2 | shAkt2 | ↓ Migration, invasion & lung metastases | ↓ F-Actin & vimentin | ||
| Akt1 | MCF-10A, MCF-7 and BT474 cells | Akt1 siRNA | ↑ EMT | ↓ miR-200, ↑ Zeb1, ↓ E-cadherin | [94] |
| MMTV-cErbB2 mice | Akt1 knockout | ↑ Migration & invasion | |||
| Akt1 | MCF-7, BT-474, MDA-MB-231, SKBR3 | Akt1 siRNA | ↑ EMT and invasion | ↑ EGFR/ERK activity, >↑ Nuclear β-catenin | [95] |
| Akt2 | MDA-MB-231, MDA-MB-468, MCF-7, | Akt2 siRNA | ↓ Non-CSC reversion, ↓ CSC survival | ↓ Twist, ↓ mTOR | [96] |
| SKBR-3 cells & MDA-MB-231 xenografts | ↓ EMT and invasion | ||||
| Akt1 | MCF-10A, p53-null background, MCF-7 | Akt1 E17K | ↑ Cell growth, ↓ Migration & invasion | ↓ Zeb1, ↑ E-cadherin | [97] |
| Akt2 | Myr-Akt2 | ↑ β-catenin transcription, ↓ E-cadherin | |||
| Akt3 | MDA-MB-231 BO cells & xenografts | Akt3 siRNA | ↑ Migration, invasion and bone metastasis | ↑ HER2 and DDR kinase, ↓ CTGF | [98] |
| Akt1 | Transgenic MMTV-ErbB2 mice | Akt1 knockout | ↓ Cell proliferation, ↓ Tumor growth | ↓ p21, p27 & cyclin D1 | [99] |
| Monolayer & 3D culture of MEC | ↓ Cell migration and Lung metastases | ↓TSC2 phosphorylation (S939), ↓CXCL-16 | |||
| Akt1 | MMTV-ErbB2 & MMTV-PyMT mice | Akt1 knockout | ↓Tumorigenesis, ↑ Invasion, ↓Lung metastases | ↓Cyclin D1 | [100] |
| Akt2 | Akt2 knockout | ↑ Tumorigenesis, ↓metastases | ↑ Cyclin D1 | ||
| Akt3 | Akt3 knockout | No effect on tumorigenesis or lung metastases | |||
| Akt1 | Immortalized MEC | Akt1 and vAkt1 | ↑ Invasion | ↓ MMP2 degradation | [101] |
| Akt1 | IBC cells-SUM149 | Akt1 siRNA | ↓ IBC cell invasion, no effect in nIBC cells | ↓ RhoC GTPase activity | [102] |
| Akt2 | nIBC cells-MDA-MB-231 & * MDA-MB-435 | Akt2 siRNA | ↓ nIBC cell invasion, no effect in IBC cells | ||
| Akt3 siRNA | ↓ Survival of IBC but not nIBC cells | ||||
| Akt3 | No effect on invasion in IBC & nIBC cells | ||||
| Akt1 | HER2-enriched MMTV-NIC mouse model | Cell-autonomous Akt1 deletion | ↓ Tumor development, No effect on lung metastasis | [103] | |
| Akt2 | Cell-autonomous Akt2 deletion | ↓ Tumor development completely | |||
| Akt1 | HER2-enriched MMTV-ErbB2 mouse model | Systemic Akt1 deletion | ↓ Tumor growth, ↓ metastasis completely | ||
| Akt2 | Systemic Akt2 deletion | ↑ Tumor growth, ↑ metastasis markedly | ↑ Insulin, ↑ ErbB2, ↑ Akt1 activity | ||
| Akt1 | Luminal B MMTV-PyMT mouse model | Cell-autonomous Akt1 deletion | No effect on metastasis | ||
| Akt2 | Cell-autonomous Akt2 deletion | No effect on metastasis | |||
| Akt1 | Luminal B MMTV-PyMT mouse model | Systemic Akt1 deletion | Improved tumor-free survival, ↓ lung metastasis | ↓ Survival & mobilization of neutrophil | |
| Akt2 | Systemic Akt2 deletion | No effect on survival or lung metastasis | ↑ Akt1 activity |
* Please note that although MDA-MB-435 cells were originally isolated as breast cancer cells, based on cell authentication they are now characterized as melanoma cells.