LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective

Overview

Journal Oxid Med Cell Longev

Publisher Wiley

Specialties Cell Biology
Endocrinology

Date 2019 Nov 30

PMID 31781355

Citations 61

Authors

Francesco Ciccarese

Elisabetta Zulato

Stefano Indraccolo

Affiliations

Soon will be listed here.

Abstract

Inactivating mutations of the tumor suppressor gene Liver Kinase B1 () are frequently detected in non-small-cell lung cancer (NSCLC) and cervical carcinoma. Moreover, LKB1 expression is epigenetically regulated in several tumor types. LKB1 has an established function in the control of cell metabolism and oxidative stress. Clinical and preclinical studies support a role of LKB1 as a central modifier of cellular response to different stress-inducing drugs, suggesting LKB1 pathway as a highly promising therapeutic target. Loss of LKB1-AMPK signaling confers sensitivity to energy depletion and to redox homeostasis impairment and has been associated with an improved outcome in advanced NSCLC patients treated with chemotherapy. In this review, we provide an overview of the interplay between LKB1 and its downstream targets in cancer and focus on potential therapeutic strategies whose outcome could depend from LKB1.

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References

Mehenni H, Gehrig C, Nezu J, Oku A, SHIMANE M, Rossier C . Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity. Am J Hum Genet. 1998; 63(6):1641-50. PMC: 1377635. DOI: 10.1086/302159. View

Trapp E, Majunke L, Zill B, Sommer H, Andergassen U, Koch J . LKB1 pro-oncogenic activity triggers cell survival in circulating tumor cells. Mol Oncol. 2017; 11(11):1508-1526. PMC: 5663996. DOI: 10.1002/1878-0261.12111. View

Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z . AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 2013; 17(1):113-24. PMC: 3545102. DOI: 10.1016/j.cmet.2012.12.001. View

Molenaar R, Coelen R, Khurshed M, Roos E, Caan M, van Linde M . Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with -mutated or -mutated solid tumours. BMJ Open. 2017; 7(6):e014961. PMC: 5541450. DOI: 10.1136/bmjopen-2016-014961. View

Souroullas G, Fedoriw Y, Staudt L, Sharpless N . Lkb1 deletion in murine B lymphocytes promotes cell death and cancer. Exp Hematol. 2017; 51:63-70.e1. PMC: 5554940. DOI: 10.1016/j.exphem.2017.04.005. View

Bin-Umer M, McLaughlin J, Butterly M, McCormick S, Tumer N . Elimination of damaged mitochondria through mitophagy reduces mitochondrial oxidative stress and increases tolerance to trichothecenes. Proc Natl Acad Sci U S A. 2014; 111(32):11798-803. PMC: 4136610. DOI: 10.1073/pnas.1403145111. View

Shackelford D, Vasquez D, Corbeil J, Wu S, Leblanc M, Wu C . mTOR and HIF-1alpha-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome. Proc Natl Acad Sci U S A. 2009; 106(27):11137-42. PMC: 2708689. DOI: 10.1073/pnas.0900465106. View

Zhang P, Lai Z, Chen H, Zhang M, Wang A, Jia T . Curcumin synergizes with 5-fluorouracil by impairing AMPK/ULK1-dependent autophagy, AKT activity and enhancing apoptosis in colon cancer cells with tumor growth inhibition in xenograft mice. J Exp Clin Cancer Res. 2017; 36(1):190. PMC: 5741949. DOI: 10.1186/s13046-017-0661-7. View

Jenne D, Reimann H, Nezu J, FRIEDEL W, Loff S, Jeschke R . Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet. 1998; 18(1):38-43. DOI: 10.1038/ng0198-38. View

10.

Kang S, Haydar G, Taniane C, Farrell G, Arias I, Lippincott-Schwartz J . AMPK Activation Prevents and Reverses Drug-Induced Mitochondrial and Hepatocyte Injury by Promoting Mitochondrial Fusion and Function. PLoS One. 2016; 11(10):e0165638. PMC: 5085033. DOI: 10.1371/journal.pone.0165638. View

11.

Sharma V, Raimondi V, Ruggero K, Pise-Masison C, Cavallari I, Silic-Benussi M . Expression of miR-34a in T-Cells Infected by Human T-Lymphotropic Virus 1. Front Microbiol. 2018; 9:832. PMC: 5945834. DOI: 10.3389/fmicb.2018.00832. View

12.

Xu H, Zhai Y, Chen J, Lu Y, Wang J, Quan C . LKB1 reduces ROS-mediated cell damage via activation of p38. Oncogene. 2014; 34(29):3848-59. PMC: 4377312. DOI: 10.1038/onc.2014.315. View

13.

Fu X, Wan S, Lyu Y, Liu L, Qi H . Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation. PLoS One. 2008; 3(4):e2009. PMC: 2329593. DOI: 10.1371/journal.pone.0002009. View

14.

Zulato E, Ciccarese F, Nardo G, Pinazza M, Agnusdei V, Silic-Benussi M . Involvement of NADPH Oxidase 1 in Liver Kinase B1-Mediated Effects on Tumor Angiogenesis and Growth. Front Oncol. 2018; 8:195. PMC: 5994402. DOI: 10.3389/fonc.2018.00195. View

15.

Zhang H, Liu B, Li T, Zhu Y, Luo G, Jiang Y . AMPK activation serves a critical role in mitochondria quality control via modulating mitophagy in the heart under chronic hypoxia. Int J Mol Med. 2017; 41(1):69-76. PMC: 5746297. DOI: 10.3892/ijmm.2017.3213. View

16.

Maryanovich M, Gross A . A ROS rheostat for cell fate regulation. Trends Cell Biol. 2012; 23(3):129-34. DOI: 10.1016/j.tcb.2012.09.007. View

17.

Gan B, Hu J, Jiang S, Liu Y, Sahin E, Zhuang L . Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature. 2010; 468(7324):701-4. PMC: 3058342. DOI: 10.1038/nature09595. View

18.

Wu S, Wei Y . AMPK-mediated increase of glycolysis as an adaptive response to oxidative stress in human cells: implication of the cell survival in mitochondrial diseases. Biochim Biophys Acta. 2011; 1822(2):233-47. DOI: 10.1016/j.bbadis.2011.09.014. View

19.

Inge L, Friel J, Richer A, Fowler A, Whitsett T, Smith M . LKB1 inactivation sensitizes non-small cell lung cancer to pharmacological aggravation of ER stress. Cancer Lett. 2014; 352(2):187-95. DOI: 10.1016/j.canlet.2014.06.011. View

20.

Wingo S, Gallardo T, Akbay E, Liang M, Contreras C, Boren T . Somatic LKB1 mutations promote cervical cancer progression. PLoS One. 2009; 4(4):e5137. PMC: 2660434. DOI: 10.1371/journal.pone.0005137. View