Expression and Localisation of Akt-1, Akt-2 and Akt-3 Correlate with Clinical Outcome of Prostate Cancer Patients

Overview

Journal Br J Cancer

Specialty Oncology

Date 2006 May 25

PMID 16721361

Citations 40

Authors

C Le Page

I H Koumakpayi

M Alam-Fahmy

A-M Mes-Masson

F Saad

Affiliations

Soon will be listed here.

Abstract

We investigated the correlation between the expression and localisation of Akt-1, Akt-2, Akt-3, phospho-Akt proteins and the clinicopathological parameters in 63 prostate cancer specimens. More than 60% of cancerous tissues overexpressed Akt-1, Akt-2 or Akt-3. Cytoplasmic Akt-1 expression was correlated with a higher risk of postoperative prostate-specific antigen (PSA) recurrence and shorter PSA recurrence interval. Cytoplasmic Akt-2 did not show any significant correlation with clinicopathological parameters predicting outcomes. Cytoplasmic Akt-3 was associated with hormone-refractory disease progression and extracapsular invasion. Nuclear Akt-1 and Akt-2 expression were correlated with favourable outcome parameters such as absence of lymph node and perineural invasion. Kaplan-Meier analysis and Cox regression model also showed that Akt-1 and Akt-2, but not Akt-3 or phospho-Akt was associated with a significantly higher risk of PSA recurrence. In contrast, nuclear Akt-1 was significantly associated with a lower risk of PSA recurrence. Multivariate analysis revealed that clinical stage, Gleason score and the combined cytoplasmic nuclear Akt-1 marker in cancerous tissues were significant independent prognostic factors of PSA recurrence. This is the first report demonstrating in patients with prostate cancer and the particular role of Akt-1 isoform expression as a prognostic marker depending of its localisation.

Citing Articles

Interleukin-1β/Interleukin (IL)-1-Receptor-Antagonist (IL1-RA) Axis in Invasive Bladder Cancer-An Exploratory Analysis of Clinical and Tumor Biological Significance.

Vukovic M, Chamlati J, Hennenlotter J, Todenhofer T, Lutfrenk T, Jersinovic S Int J Mol Sci. 2024; 25(4).

PMID: 38397123 PMC: 10889501. DOI: 10.3390/ijms25042447.

The Role of Perineural Invasion in Prostate Cancer and Its Prognostic Significance.

Niu Y, Forster S, Muders M Cancers (Basel). 2022; 14(17).

PMID: 36077602 PMC: 9454778. DOI: 10.3390/cancers14174065.

Diarylpentanoid (1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one) (MS13) Exhibits Anti-proliferative, Apoptosis Induction and Anti-migration Properties on Androgen-independent Human Prostate Cancer by Targeting Cell Cycle-Apoptosis and PI3K....

Abd Wahab N, Abas F, Othman I, Naidu R Front Pharmacol. 2021; 12:707335.

PMID: 34366863 PMC: 8343533. DOI: 10.3389/fphar.2021.707335.

Increased Expression of AKT3 in Neuroendocrine Differentiated Prostate Cancer Cells Alters the Response Towards Anti-Androgen Treatment.

Wiesehofer M, Czyrnik E, Spahn M, Ting S, Reis H, Dankert J Cancers (Basel). 2021; 13(3).

PMID: 33540707 PMC: 7867287. DOI: 10.3390/cancers13030578.

and Variations in Childhood T-Cell Acute Lymphoblastic Leukemia.

Kucukcankurt F, Erbilgin Y, Firtina S, Ng O, Karakas Z, Celkan T Turk J Haematol. 2019; 37(2):98-103.

PMID: 31744268 PMC: 7236415. DOI: 10.4274/tjh.galenos.2019.2019.0282.

References

Lin H, Yeh S, Kang H, Chang C . Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci U S A. 2001; 98(13):7200-5. PMC: 34646. DOI: 10.1073/pnas.121173298. View

Le Page C, Koumakpayi I, Lessard L, Saad F, Mes-Masson A . Independent role of phosphoinositol-3-kinase (PI3K) and casein kinase II (CK-2) in EGFR and Her-2-mediated constitutive NF-kappaB activation in prostate cancer cells. Prostate. 2005; 65(4):306-15. DOI: 10.1002/pros.20291. View

Murillo H, Huang H, Schmidt L, Smith D, Tindall D . Role of PI3K signaling in survival and progression of LNCaP prostate cancer cells to the androgen refractory state. Endocrinology. 2001; 142(11):4795-805. DOI: 10.1210/endo.142.11.8467. View

Stal O . Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer. 2002; 86(4):540-5. PMC: 2375266. DOI: 10.1038/sj.bjc.6600126. View

Nicholson K, Anderson N . The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal. 2002; 14(5):381-95. DOI: 10.1016/s0898-6568(01)00271-6. View

Graff J . Emerging targets in the AKT pathway for treatment of androgen-independent prostatic adenocarcinoma. Expert Opin Ther Targets. 2002; 6(1):103-13. DOI: 10.1517/14728222.6.1.103. View

Malik S, Brattain M, Ghosh P, Troyer D, Prihoda T, Bedolla R . Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin Cancer Res. 2002; 8(4):1168-71. View

Ermoian R, Furniss C, Lamborn K, Basila D, Berger M, Gottschalk A . Dysregulation of PTEN and protein kinase B is associated with glioma histology and patient survival. Clin Cancer Res. 2002; 8(5):1100-6. View

Vanhaesebroeck B, Alessi D . The PI3K-PDK1 connection: more than just a road to PKB. Biochem J. 2000; 346 Pt 3:561-76. PMC: 1220886. View

10.

Graff J, Konicek B, McNulty A, Wang Z, Houck K, Allen S . Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem. 2000; 275(32):24500-5. DOI: 10.1074/jbc.M003145200. View

11.

Li Y, Sarkar F . Inhibition of nuclear factor kappaB activation in PC3 cells by genistein is mediated via Akt signaling pathway. Clin Cancer Res. 2002; 8(7):2369-77. View

12.

Lin H, Wang L, Hu Y, Altuwaijri S, Chang C . Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase. EMBO J. 2002; 21(15):4037-48. PMC: 126152. DOI: 10.1093/emboj/cdf406. View

13.

Shin I, Yakes F, Rojo F, Shin N, Bakin A, Baselga J . PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med. 2002; 8(10):1145-52. DOI: 10.1038/nm759. View

14.

Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor M, Han K . PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med. 2002; 8(10):1153-60. DOI: 10.1038/nm761. View

15.

Viglietto G, Motti M, Bruni P, Melillo R, DAlessio A, Califano D . Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med. 2002; 8(10):1136-44. DOI: 10.1038/nm762. View

16.

Horiguchi A, Oya M, Uchida A, Marumo K, Murai M . Elevated Akt activation and its impact on clinicopathological features of renal cell carcinoma. J Urol. 2003; 169(2):710-3. DOI: 10.1097/01.ju.0000038952.59355.b2. View

17.

Liao Y, Grobholz R, Abel U, Trojan L, Michel M, Angel P . Increase of AKT/PKB expression correlates with gleason pattern in human prostate cancer. Int J Cancer. 2003; 107(4):676-80. DOI: 10.1002/ijc.11471. View

18.

Vasko V, Saji M, Hardy E, Kruhlak M, Larin A, Savchenko V . Akt activation and localisation correlate with tumour invasion and oncogene expression in thyroid cancer. J Med Genet. 2004; 41(3):161-70. PMC: 1735712. DOI: 10.1136/jmg.2003.015339. View

19.

Wendel H, de Stanchina E, Fridman J, Malina A, Ray S, Kogan S . Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature. 2004; 428(6980):332-7. DOI: 10.1038/nature02369. View

20.

Kreisberg J, Malik S, Prihoda T, Bedolla R, Troyer D, Kreisberg S . Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer. Cancer Res. 2004; 64(15):5232-6. DOI: 10.1158/0008-5472.CAN-04-0272. View