Radiotherapy Diagnostic Biomarkers in Radioresistant Human H460 Lung Cancer Stem-like Cells

Overview

Journal Cancer Biol Ther

Specialties Oncology
Pharmacology

Date 2016 Feb 23

PMID 26901847

Citations 20

Authors

Hong Shik Yun

Jeong-Hwa Baek

Ji-Hye Yim

Hong-Duck Um

Jong Kuk Park

Jie-Young Song

In-Chul Park

Jae-Sung Kim

Su-Jae Lee

Chang-Woo Lee

Sang-Gu Hwang

Affiliations

Soon will be listed here.

Abstract

Tumor cell radioresistance is a major contributor to radiotherapy failure, highlighting the importance of identifying predictive biomarkers for radioresistance. In this work, we established a radioresistant H460 (RR-H460) cell line from parental radiosensitive H460 lung cancer cells by exposure to fractionated radiation. The radiation-resistant, anti-apoptotic phenotype of RR-H460 cell lines was confirmed by their enhanced clonogenic survival and increased expression of the radioresistance genes Hsp90 and Her-3. RR-H460 cells displayed characteristics of cancer stem-like cells (CSCs), including induction of the surface marker CD44 and stem cell markers Nanog, Oct4, and Sox2. RR-H460 cells also exhibited sphere formation and malignant behavior, further supporting a CSC phenotype. Using proteomic analyses, we identified 8 proteins that were up-regulated in RR-H460 CSC lines and therefore potentially involved in radioresistance and CSC-related biological processes. Notably, 4 of these-PAI-2, NOMO2, KLC4, and PLOD3-have not been previously linked to radioresistance. Depletion of these individual genes sensitized RR-H460 cells to radiotoxicity and additively enhancing radiation-induced apoptosis. Our findings suggest the possibility of integrating molecular targeted therapy with radiotherapy as a strategy for resolving the radioresistance of lung tumors.

Citing Articles

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References

Yun H, Hong E, Lee S, Baek J, Lee C, Yim J . Depletion of hepatoma-derived growth factor-related protein-3 induces apoptotic sensitization of radioresistant A549 cells via reactive oxygen species-dependent p53 activation. Biochem Biophys Res Commun. 2013; 439(3):333-9. DOI: 10.1016/j.bbrc.2013.08.086. View

Anglim P, Alonzo T, Laird-Offringa I . DNA methylation-based biomarkers for early detection of non-small cell lung cancer: an update. Mol Cancer. 2008; 7:81. PMC: 2585582. DOI: 10.1186/1476-4598-7-81. View

Lazzari C, Spitaleri G, Catania C, Barberis M, Noberasco C, Santarpia M . Targeting ALK in patients with advanced non small cell lung cancer: biology, diagnostic and therapeutic options. Crit Rev Oncol Hematol. 2013; 89(3):358-65. DOI: 10.1016/j.critrevonc.2013.09.003. View

Camphausen K, Tofilon P . Inhibition of Hsp90: a multitarget approach to radiosensitization. Clin Cancer Res. 2007; 13(15 Pt 1):4326-30. DOI: 10.1158/1078-0432.CCR-07-0632. View

Hirokawa N, Noda Y, Tanaka Y, Niwa S . Kinesin superfamily motor proteins and intracellular transport. Nat Rev Mol Cell Biol. 2009; 10(10):682-96. DOI: 10.1038/nrm2774. View

Biard D, Martin M, Rhun Y, Duthu A, Lefaix J, May E . Concomitant p53 gene mutation and increased radiosensitivity in rat lung embryo epithelial cells during neoplastic development. Cancer Res. 1994; 54(13):3361-4. View

Sirzen F, Kjellen E, Sorenson S, Cavallin-Stahl E . A systematic overview of radiation therapy effects in non-small cell lung cancer. Acta Oncol. 2003; 42(5-6):493-515. DOI: 10.1080/02841860310014453. View

Levina V, Marrangoni A, DeMarco R, Gorelik E, Lokshin A . Drug-selected human lung cancer stem cells: cytokine network, tumorigenic and metastatic properties. PLoS One. 2008; 3(8):e3077. PMC: 2518121. DOI: 10.1371/journal.pone.0003077. View

Contessa J, Abell A, Mikkelsen R, Valerie K, Schmidt-Ullrich R . Compensatory ErbB3/c-Src signaling enhances carcinoma cell survival to ionizing radiation. Breast Cancer Res Treat. 2005; 95(1):17-27. DOI: 10.1007/s10549-005-9023-9. View

10.

Vivanco I, Sawyers C . The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002; 2(7):489-501. DOI: 10.1038/nrc839. View

11.

Kim J, Chang J, Park J, Hwang S . Increased aldehyde reductase expression mediates acquired radioresistance of laryngeal cancer cells via modulating p53. Cancer Biol Ther. 2012; 13(8):638-46. DOI: 10.4161/cbt.20081. View

12.

Tapio S, Danescu-Mayer J, Asmuss M, Posch A, Gomolka M, Hornhardt S . Combined effects of gamma radiation and arsenite on the proteome of human TK6 lymphoblastoid cells. Mutat Res. 2005; 581(1-2):141-52. DOI: 10.1016/j.mrgentox.2004.11.016. View

13.

Wei R, Zhang Y, Shen L, Jiang W, Li C, Zhong M . Comparative proteomic and radiobiological analyses in human lung adenocarcinoma cells. Mol Cell Biochem. 2011; 359(1-2):151-9. DOI: 10.1007/s11010-011-1008-x. View

14.

Kim I, Bae S, Fernandes A, Wu J, Muschel R, McKenna W . Selective inhibition of Ras, phosphoinositide 3 kinase, and Akt isoforms increases the radiosensitivity of human carcinoma cell lines. Cancer Res. 2005; 65(17):7902-10. DOI: 10.1158/0008-5472.CAN-05-0513. View

15.

Guo W, Lin R, Huang J, Zhou Z, Yang J, Guo G . Identification of differentially expressed genes contributing to radioresistance in lung cancer cells using microarray analysis. Radiat Res. 2005; 164(1):27-35. DOI: 10.1667/rr3401. View

16.

Kao Y, Lee S, Lin L, Chen L, Hsing C, Hsu H . Fatty acid synthase overexpression confers an independent prognosticator and associates with radiation resistance in nasopharyngeal carcinoma. Tumour Biol. 2012; 34(2):759-68. DOI: 10.1007/s13277-012-0605-y. View

17.

Srinivas P, Kramer B, Srivastava S . Trends in biomarker research for cancer detection. Lancet Oncol. 2002; 2(11):698-704. DOI: 10.1016/S1470-2045(01)00560-5. View

18.

Lee Y, Oh J, Yoon S, Kwon M, Song C, Kim K . Differential gene expression profiles of radioresistant non-small-cell lung cancer cell lines established by fractionated irradiation: tumor protein p53-inducible protein 3 confers sensitivity to ionizing radiation. Int J Radiat Oncol Biol Phys. 2010; 77(3):858-66. DOI: 10.1016/j.ijrobp.2009.12.076. View

19.

Dickinson J, Bates E, Ferrante A, Antalis T . Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor alpha-induced apoptosis. Evidence for an alternate biological function. J Biol Chem. 1995; 270(46):27894-904. DOI: 10.1074/jbc.270.46.27894. View

20.

Nojiri K, Iwakawa M, Ichikawa Y, Imadome K, Sakai M, Nakawatari M . The proangiogenic factor ephrin-A1 is up-regulated in radioresistant murine tumor by irradiation. Exp Biol Med (Maywood). 2008; 234(1):112-22. DOI: 10.3181/0806-RM-189. View