Over-expressions of AMPK Subunits in Ovarian Carcinomas with Significant Clinical Implications

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2012 Aug 18

PMID 22897928

Citations 29

Authors

Cuilan Li

Vincent Ws Liu

Pui M Chiu

David W Chan

Hextan Ys Ngan

Affiliations

Soon will be listed here.

Abstract

Background: AMP-activated protein kinase (AMPK) has recently been considered as a potential target for cancer therapy. However, the expression status of various subunits of the heterotrimeric AMPK in human cancers is rarely reported. We decided to determine their expressions in ovarian carcinomas and their relationships with the disease.

Methods: Expressions and locations of the AMPK-α1, -α2, -β1, -β2, -γ1 and -γ2 were detected by quantitative PCR (Q-PCR) and immunohistochemical staining (IHC). Their expression levels in ovarian tumors were compared with normal controls and also correlated with clinicopathological parameters.

Results: Except AMPK-α1, expressions of the other five AMPK subunits are significantly higher in ovarian carcinomas as determined by Q-PCR. Although IHC detection of AMPK-γ1 and -γ2 were not successful, over-expressions of AMPK-α2, -β1, and -β2 were further confirmed by IHC. Over-expressions of various AMPK subunits occurred independently and were mainly detected in the cytoplasm. Interestingly, AMPK-α2 and -β1 were also detected in the nucleus and cell membrane, respectively. Clinical correlation analyses indicate that expressions of different AMPK subunits are associated with different subtypes of carcinoma. High expression of AMPK-α2 is significantly associated with endometrioid carcinomas. On the other hand, high expressions of AMPK-β and -γ subunits are associated with mucinous and serous carcinomas, respectively. Furthermore, high expressions of AMPK-β1 and -γ2 are also associated with early and late stages of disease, respectively. Finally, patients with high expression of AMPK-α2 had better prognosis.

Conclusions: Aberrant expressions of AMPK subunits may play important roles in ovarian carcinogenesis. Each AMPK subunit may have its own function other than just a component of the AMPK molecule. Correlations with clinical parameters suggest that expressions of AMPK subunits have different clinical implications in ovarian cancer development.

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References

Neurath K, Keough M, Mikkelsen T, Claffey K . AMP-dependent protein kinase alpha 2 isoform promotes hypoxia-induced VEGF expression in human glioblastoma. Glia. 2006; 53(7):733-43. DOI: 10.1002/glia.20326. View

Lee Y, Lee S, Sin H, Kim E, Um S . Kinase activity-independent suppression of p73alpha by AMP-activated kinase alpha (AMPKalpha). Oncogene. 2008; 28(7):1040-52. DOI: 10.1038/onc.2008.452. View

Steinberg G, Kemp B . AMPK in Health and Disease. Physiol Rev. 2009; 89(3):1025-78. DOI: 10.1152/physrev.00011.2008. View

Yu S, Chan D, Liu V, Ngan H . Inhibition of cervical cancer cell growth through activation of upstream kinases of AMP-activated protein kinase. Tumour Biol. 2009; 30(2):80-5. DOI: 10.1159/000216843. View

Li J, Jiang P, Robinson M, Lawrence T, Sun Y . AMPK-beta1 subunit is a p53-independent stress responsive protein that inhibits tumor cell growth upon forced expression. Carcinogenesis. 2003; 24(5):827-34. DOI: 10.1093/carcin/bgg032. View

Gotlieb W, Saumet J, Beauchamp M, Gu J, Lau S, Pollak M . In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecol Oncol. 2008; 110(2):246-50. DOI: 10.1016/j.ygyno.2008.04.008. View

Schmittgen T, Livak K . Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008; 3(6):1101-8. DOI: 10.1038/nprot.2008.73. View

Shackelford D, Shaw R . The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009; 9(8):563-75. PMC: 2756045. DOI: 10.1038/nrc2676. View

Fogarty S, Hardie D . Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer. Biochim Biophys Acta. 2009; 1804(3):581-91. DOI: 10.1016/j.bbapap.2009.09.012. View

10.

Wang Y, Chan D, Liu V, Chiu P, Ngan H . Differential functions of growth factor receptor-bound protein 7 (GRB7) and its variant GRB7v in ovarian carcinogenesis. Clin Cancer Res. 2010; 16(9):2529-39. DOI: 10.1158/1078-0432.CCR-10-0018. View

11.

Huang F, Chiu P, Tam K, Kwok Y, Lau E, Tang M . Semi-quantitative fluorescent PCR analysis identifies PRKAA1 on chromosome 5 as a potential candidate cancer gene of cervical cancer. Gynecol Oncol. 2006; 103(1):219-25. DOI: 10.1016/j.ygyno.2006.02.028. View

12.

Grahame Hardie D . AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007; 8(10):774-85. DOI: 10.1038/nrm2249. View

13.

Brenman J . AMPK/LKB1 signaling in epithelial cell polarity and cell division. Cell Cycle. 2007; 6(22):2755-9. DOI: 10.4161/cc.6.22.4927. View

14.

Yasmeen A, Beauchamp M, Piura E, Segal E, Pollak M, Gotlieb W . Induction of apoptosis by metformin in epithelial ovarian cancer: involvement of the Bcl-2 family proteins. Gynecol Oncol. 2011; 121(3):492-8. DOI: 10.1016/j.ygyno.2011.02.021. View

15.

Hallstrom T, Mori S, Nevins J . An E2F1-dependent gene expression program that determines the balance between proliferation and cell death. Cancer Cell. 2008; 13(1):11-22. PMC: 2243238. DOI: 10.1016/j.ccr.2007.11.031. View

16.

Rattan R, Giri S, Hartmann L, Shridhar V . Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med. 2009; 15(1):166-78. PMC: 3822503. DOI: 10.1111/j.1582-4934.2009.00954.x. View