The Tumor Suppressor Gene TUSC2 (FUS1) Sensitizes NSCLC to the AKT Inhibitor MK2206 in LKB1-dependent Manner

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Oct 23

PMID 24146957

Citations 15

Authors

Jieru Meng

Mourad Majidi

Bingliang Fang

Lin Ji

B Nebiyou Bekele

John D Minna

Jack A Roth

Affiliations

Soon will be listed here.

Abstract

TUSC2-defective gene expression is detected in the majority of lung cancers and is associated with worse overall survival. We analyzed the effects of TUSC2 re-expression on tumor cell sensitivity to the AKT inhibitor, MK2206, and explored their mutual signaling connections, in vitro and in vivo. TUSC2 transient expression in three LKB1-defective non-small cell lung cancer (NSCLC) cell lines combined with MK2206 treatment resulted in increased repression of cell viability and colony formation, and increased apoptotic activity. In contrast, TUSC2 did not affect the response to MK2206 treatment for two LKB1-wild type NSCLC cell lines. In vivo, TUSC2 systemic delivery, by nanoparticle gene transfer, combined with MK2206 treatment markedly inhibited growth of tumors in a human LKB1-defective H322 lung cancer xenograft mouse model. Biochemical analysis showed that TUSC2 transient expression in LKB1-defective NSCLC cells significantly stimulated AMP-activated protein kinase (AMPK) phosphorylation and enzymatic activity. More importantly, AMPK gene knockdown abrogated TUSC2-MK2206 cooperation, as evidenced by reduced sensitivity to the combined treatment. Together, TUSC2 re-expression and MK2206 treatment was more effective in inhibiting the phosphorylation and kinase activities of AKT and mTOR proteins than either single agent alone. In conclusion, these findings support the hypothesis that TUSC2 expression status is a biological variable that potentiates MK2206 sensitivity in LKB1-defective NSCLC cells, and identifies the AMPK/AKT/mTOR signaling axis as an important regulator of this activity.

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References

Prudkin L, Behrens C, Liu D, Zhou X, Ozburn N, Bekele B . Loss and reduction of FUS1 protein expression is a frequent phenomenon in the pathogenesis of lung cancer. Clin Cancer Res. 2008; 14(1):41-7. PMC: 2833352. DOI: 10.1158/1078-0432.CCR-07-1252. View

Ito I, Ji L, Tanaka F, Saito Y, Gopalan B, Branch C . Liposomal vector mediated delivery of the 3p FUS1 gene demonstrates potent antitumor activity against human lung cancer in vivo. Cancer Gene Ther. 2004; 11(11):733-9. DOI: 10.1038/sj.cgt.7700756. View

Aoki M, Blazek E, Vogt P . A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt. Proc Natl Acad Sci U S A. 2001; 98(1):136-41. PMC: 14557. DOI: 10.1073/pnas.98.1.136. View

King T, Song L, Jope R . AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3. Biochem Pharmacol. 2006; 71(11):1637-47. PMC: 1618797. DOI: 10.1016/j.bcp.2006.03.005. View

Shah U, Sharpless N, Hayes D . LKB1 and lung cancer: more than the usual suspects. Cancer Res. 2008; 68(10):3562-5. DOI: 10.1158/0008-5472.CAN-07-6620. View

Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I . EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004; 101(36):13306-11. PMC: 516528. DOI: 10.1073/pnas.0405220101. View

Ciardiello F, Caputo R, Bianco R, Damiano V, Fontanini G, Cuccato S . Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res. 2001; 7(5):1459-65. View

Ji L, Nishizaki M, Gao B, Burbee D, Kondo M, Kamibayashi C . Expression of several genes in the human chromosome 3p21.3 homozygous deletion region by an adenovirus vector results in tumor suppressor activities in vitro and in vivo. Cancer Res. 2002; 62(9):2715-20. PMC: 3478680. 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

10.

Bortul R, Tazzari P, Cappellini A, Tabellini G, Billi A, Bareggi R . Constitutively active Akt1 protects HL60 leukemia cells from TRAIL-induced apoptosis through a mechanism involving NF-kappaB activation and cFLIP(L) up-regulation. Leukemia. 2003; 17(2):379-89. DOI: 10.1038/sj.leu.2402793. View

11.

Ji L, Roth J . Tumor suppressor FUS1 signaling pathway. J Thorac Oncol. 2008; 3(4):327-30. PMC: 3370667. DOI: 10.1097/JTO.0b013e31816bce65. View

12.

Lin J, Sun T, Ji L, Deng W, Roth J, Minna J . Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking FUS1 expression: inhibition of c-Abl by the tumor suppressor gene product Fus1. Oncogene. 2007; 26(49):6989-96. PMC: 3457636. DOI: 10.1038/sj.onc.1210500. View

13.

Lerman M, Minna J . The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium. Cancer Res. 2000; 60(21):6116-33. View

14.

Ivanova A, Ivanov S, Prudkin L, Nonaka D, Liu Z, Tsao A . Mechanisms of FUS1/TUSC2 deficiency in mesothelioma and its tumorigenic transcriptional effects. Mol Cancer. 2009; 8:91. PMC: 2776015. DOI: 10.1186/1476-4598-8-91. View

15.

Li G, Kawashima H, Ji L, Ogose A, Ariizumi T, Umezu H . Frequent absence of tumor suppressor FUS1 protein expression in human bone and soft tissue sarcomas. Anticancer Res. 2011; 31(1):11-21. View

16.

Ono M, Hirata A, Kometani T, Miyagawa M, Ueda S, Kinoshita H . Sensitivity to gefitinib (Iressa, ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor (EGF) receptor/extracellular signal-regulated kinase 1/2 and EGF receptor/Akt pathway for proliferation. Mol Cancer Ther. 2004; 3(4):465-72. View

17.

Hesson L, Cooper W, Latif F . Evaluation of the 3p21.3 tumour-suppressor gene cluster. Oncogene. 2007; 26(52):7283-301. DOI: 10.1038/sj.onc.1210547. View

18.

Gopalan B, Ito I, Branch C, Stephens C, Roth J, Ramesh R . Nanoparticle based systemic gene therapy for lung cancer: molecular mechanisms and strategies to suppress nanoparticle-mediated inflammatory response. Technol Cancer Res Treat. 2004; 3(6):647-57. DOI: 10.1177/153303460400300615. View

19.

Hidalgo M, Siu L, Nemunaitis J, Rizzo J, Hammond L, Takimoto C . Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol. 2001; 19(13):3267-79. DOI: 10.1200/JCO.2001.19.13.3267. View

20.

Paez J, Janne P, Lee J, Tracy S, Greulich H, Gabriel S . EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004; 304(5676):1497-500. DOI: 10.1126/science.1099314. View