Exogenous activation of LKB1/AMPK signaling induces G1 arrest in cells with endogenous LKB1 expression

Liang,Xiaoyan; Wang,Pilong; Gao,Qing; Tao,Xiaohong

doi:10.3892/mmr.2014.1916

2014-March Volume 9 Issue 3

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

2014-March Volume 9 Issue 3

Full Size Image

Article

Exogenous activation of LKB1/AMPK signaling induces G1 arrest in cells with endogenous LKB1 expression

Authors:
- Xiaoyan Liang
- Pilong Wang
- Qing Gao
- Xiaohong Tao
View Affiliations / Copyright

Affiliations: Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
Pages: 1019-1024
|
Published online on: January 23, 2014

https://doi.org/10.3892/mmr.2014.1916
Expand metrics +

Abstract

The tumor suppressor protein LKB1 is a serine/threonine kinase that plays a critical role in cell proliferation, and its inactivation has been linked to tumorigenesis in various cancer types. Current understanding of the LKB1 function is largely restricted to results from experiments on LKB1‑deficient cancer cells, while the regulation and activity of endogenous LKB1 has been rarely investigated. In a previous study, we showed that LKB1 knockdown in two healthy cell lines accelerates cell cycle progression through the G1/S checkpoint by inhibition of the p53 and p16 pathways. In the present study, we examined the effects of overexpression of LKB1 on two healthy and one cancer cell line. Administration of exogenous LKB1 activated LKB1/AMPK signaling and arrested the cell cycle at the G1 phase in an LKB1-dependent manner. G1 arrest induced by LKB1 was accompanied by the downregulation of cyclin D1 and cyclin D3, and the upregulation of p53, p21 and p16, while no differences were detected for CDK4, CDK6, cyclin E, p15 and p27. These results indicated that exogenous activation of LKB1/AMPK signaling inhibits the G1/S cell cycle transition, even in cells with an endogenous expression of LKB1. Findings of the present study extend earlier observations on LKB1‑inactivated neoplastic cells and provide novel insights into the growth-inhibitory effects of LKB1.

View Figures

View References

1	McGarrity TJ and Amos C: Peutz-Jeghers syndrome: clinicopathology and molecular alterations. Cell Mol Life Sci. 63:2135–2144. 2006. View Article : Google Scholar : PubMed/NCBI
2	Rustgi AK: The genetics of hereditary colon cancer. Genes Dev. 21:2525–2538. 2007. View Article : Google Scholar : PubMed/NCBI
3	Hemminki A, Markie D, Tomlinson I, et al: A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. 391:184–187. 1998. View Article : Google Scholar : PubMed/NCBI
4	Jenne DE, Reimann H, Nezu J, et al: Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet. 18:38–43. 1998. View Article : Google Scholar : PubMed/NCBI
5	Williams T and Brenman JE: LKB1 and AMPK in cell polarity and division. Trends Cell Biol. 18:193–198. 2008. View Article : Google Scholar : PubMed/NCBI
6	Shackelford DB and Shaw RJ: The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 9:563–575. 2009. View Article : Google Scholar : PubMed/NCBI
7	Hearle N, Schumacher V, Menko FH, et al: Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res. 12:3209–3215. 2006. View Article : Google Scholar : PubMed/NCBI
8	Partanen JI, Tervonen TA, Myllynen M, et al: Tumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity. Proc Natl Acad Sci USA. 109:E388–E397. 2012. View Article : Google Scholar : PubMed/NCBI
9	Manning AL and Dyson NJ: pRB, a tumor suppressor with a stabilizing presence. Trends Cell Biol. 21:433–441. 2011. View Article : Google Scholar : PubMed/NCBI
10	Sclafani RA and Holzen TM: Cell cycle regulation of DNA replication. Annu Rev Genet. 41:237–280. 2007. View Article : Google Scholar : PubMed/NCBI
11	Tiainen M, Vaahtomeri K, Ylikorkala A and Mäkelä TP: Growth arrest by the LKB1 tumor suppressor: induction of p21(WAF1/CIP1). Hum Mol Genet. 11:1497–1504. 2002. View Article : Google Scholar : PubMed/NCBI
12	Tiainen M, Ylikorkala A and Mäkelä TP: Growth suppression by Lkb1 is mediated by a G₁ cell cycle arrest. Proc Natl Acad Sci USA. 96:9248–9251. 1999. View Article : Google Scholar : PubMed/NCBI
13	Gurumurthy S, Hezel AF, Sahin E, Berger JH, Bosenberg MW and Bardeesy N: LKB1 deficiency sensitizes mice to carcinogen-induced tumorigenesis. Cancer Res. 68:55–63. 2008. View Article : Google Scholar : PubMed/NCBI
14	Liang X, Wang P, Gao Q, Xiang T and Tao X: Endogenous LKB1 knockdown accelerates G₁/S transition through p53 and p16 pathways. Cancer Biol Ther. 9:156–160. 2010. View Article : Google Scholar : PubMed/NCBI
15	Karuman P, Gozani O, Odze RD, et al: The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death. Mol Cell. 7:1307–1319. 2001. View Article : Google Scholar : PubMed/NCBI
16	Hou X, Xu S, Maitland-Toolan KA, et al: SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem. 283:20015–20026. 2008. View Article : Google Scholar : PubMed/NCBI
17	Lizcano JM, Göransson O, Toth R, et al: LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 23:833–843. 2004. View Article : Google Scholar : PubMed/NCBI
18	Drury LS and Diffley JF: Factors affecting the diversity of DNA replication licensing control in eukaryotes. Curr Biol. 19:530–535. 2009. View Article : Google Scholar : PubMed/NCBI
19	Giacinti C and Giordano A: RB and cell cycle progression. Oncogene. 25:5220–5227. 2006. View Article : Google Scholar : PubMed/NCBI
20	Green MF, Anderson KA and Means AR: Characterization of the CaMKKβ-AMPK signaling complex. Cell Signal. 23:2005–2012. 2011.
21	Senderowicz AM: Inhibitors of cyclin-dependent kinase modulators for cancer therapy. Prog Drug Res. 63:183–206. 2005. View Article : Google Scholar : PubMed/NCBI
22	Shapiro GI: Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 24:1770–1783. 2006. View Article : Google Scholar : PubMed/NCBI
23	Cánepa ET, Scassa ME, Ceruti JM, et al: INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions. IUBMB Life. 59:419–426. 2007.PubMed/NCBI
24	Abbas T and Dutta A: p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 9:400–414. 2009. View Article : Google Scholar : PubMed/NCBI
25	Garner E and Raj K: Protective mechanisms of p53-p21-pRb proteins against DNA damage-induced cell death. Cell Cycle. 7:277–282. 2008. View Article : Google Scholar : PubMed/NCBI
26	Pei XH and Xiong Y: Biochemical and cellular mechanisms of mammalian CDK inhibitors: a few unresolved issues. Oncogene. 24:2787–2795. 2005. View Article : Google Scholar : PubMed/NCBI
27	Satyanarayana A and Rudolph KL: p16 and ARF: activation of teenage proteins in old age. J Clin Invest. 114:1237–1240. 2004. View Article : Google Scholar : PubMed/NCBI
28	Maddika S, Ande SR, Panigrahi S, et al: Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. Drug Resist Updat. 10:13–29. 2007. View Article : Google Scholar : PubMed/NCBI
29	Li J, Simpson L, Takahashi M, et al: The PTEN/MMAC1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene. Cancer Res. 58:5667–5672. 1998.PubMed/NCBI
30	Winship IM and Dudding TE: Lessons from the skin - cutaneous features of familial cancer. Lancet Oncol. 9:462–472. 2008. View Article : Google Scholar : PubMed/NCBI
31	Jass JR: Colorectal polyposes: from phenotype to diagnosis. Pathol Res Pract. 20:431–447. 2008. View Article : Google Scholar : PubMed/NCBI
32	Bheda A, Shackelford J and Pagano JS: Expression and functional studies of ubiquitin C-terminal hydrolase L1 regulated genes. PLoS One. 4:e67642009. View Article : Google Scholar : PubMed/NCBI
33	Aulestia FJ, Redondo PC, Rodríguez-García A, et al: Two distinct calcium pools in the endoplasmic reticulum of HEK-293T cells. Biochem J. 435:227–235. 2011. View Article : Google Scholar : PubMed/NCBI
34	Santi SA and Lee H: The Akt isoforms are present at distinct subcellular locations. Am J Physiol Cell Physiol. 298:C580–C591. 2010. View Article : Google Scholar : PubMed/NCBI
35	Gallagher SJ, Thompson JF, Indsto J, et al: p16INK4a expression and absence of activated B-RAF are independent predictors of chemosensitivity in melanoma tumors. Neoplasia. 10:1231–1239. 2008.PubMed/NCBI
36	Zhang Y, Xiong Y and Yarbrough WG: ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell. 92:725–734. 1998. View Article : Google Scholar : PubMed/NCBI
37	Morton JP, Jamieson NB, Karim SA, et al: LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest. Gastroenterology. 139:586–597. 5972010. View Article : Google Scholar : PubMed/NCBI
38	De Leng WW, Westerman AM, Weterman MA, et al: Cyclooxygenase 2 expression and molecular alterations in Peutz-Jeghers hamartomas and carcinomas. Clin Cancer Res. 9:3065–3072. 2003.PubMed/NCBI
39	Scott KD, Nath-Sain S, Agnew MD and Marignani PA: LKB1 catalytically deficient mutants enhance cyclin D1 expression. Cancer Res. 67:5622–5627. 2007. View Article : Google Scholar : PubMed/NCBI
40	Ji H, Ramsey MR, Hayes DN, et al: LKB1 modulates lung cancer differentiation and metastasis. Nature. 448:807–810. 2007. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Exogenous activation of LKB1/AMPK signaling induces G1 arrest in cells with endogenous LKB1 expression

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Related Articles