DHFR and MDR1 Upregulation is Associated with Chemoresistance in Osteosarcoma Stem-like Cells

Overview

Journal Oncol Lett

Specialty Oncology

Date 2017 Jul 12

PMID 28693150

Citations 16

Authors

Yu-Hsien Lee

Hui-Wen Yang

Li-Chiu Yang

Ming-Yi Lu

Lo-Lin Tsai

Shun-Fa Yang

Yu-Feng Huang

Ming-Yung Chou

Cheng-Chia Yu

Fang-Wei Hu

Affiliations

Soon will be listed here.

Abstract

Tumor-initiating cells (TICs) are defined as a specialized subset of cells with tumor-initiating capacity that can initiate tumor growth, tumor relapse and metastasis. In the present study, osteosarcoma TICs (OS-TICs) were isolated and enriched from the osteosarcoma U2OS and MG-63 cell lines using sphere formation assays and serum-depleted media. These enriched OS-TICs showed the expression of several typical cancer stemness markers, including octamer-binding transcription factor 4, Nanog homeobox, cluster of differentiation (CD)117, Nestin and CD133, and the expression of ATP binding cassette subfamily G member 2, multidrug resistance protein 1 (MDR1) and dihydrofolate reductase (DHFR). Notably, and tumorigenic properties were enhanced in these OS-TICs. Additionally, methotrexate and doxorubicin are the most widely used anticancer agents against osteosarcoma, and the observed enhanced chemoresistance of OS-TICs to these two agents could be associated with the upregulation of DHFR and MDR1. These findings suggest that the upregulation of DHFR and MDR1 is associated with the development of chemoresistance of OS-TICs.

Citing Articles

Astaxanthin Co-treatment with Low Dose Methotrexate Increases the Cell Cycle Arrest and Ameliorates the Methotrexate-induced Inflammatory Response in NALM-6.

Moridi N, Najafzadeh M, Sayedi M, Sajjadi S Int J Mol Cell Med. 2024; 13(2):133-146.

PMID: 39184820 PMC: 11344562. DOI: 10.22088/IJMCM.BUMS.13.2.133.

LncRNA EBLN3P attributes methotrexate resistance in osteosarcoma cells through miR-200a-3p/O-GlcNAc transferase pathway.

Sun M, An H, Sun Y, Sun Y, Bai B J Orthop Surg Res. 2022; 17(1):557.

PMID: 36544170 PMC: 9773527. DOI: 10.1186/s13018-022-03449-y.

Chemoresistance-Related Stem Cell Signaling in Osteosarcoma and Its Plausible Contribution to Poor Therapeutic Response: A Discussion That Still Matters.

Martins-Neves S, Sampaio-Ribeiro G, Gomes C Int J Mol Sci. 2022; 23(19).

PMID: 36232719 PMC: 9569807. DOI: 10.3390/ijms231911416.

An overview of resistance to chemotherapy in osteosarcoma and future perspectives.

Garcia-Ortega D, Cabrera-Nieto S, Caro-Sanchez H, Cruz-Ramos M Cancer Drug Resist. 2022; 5(3):762-793.

PMID: 36176756 PMC: 9511812. DOI: 10.20517/cdr.2022.18.

LncRNA in tumorigenesis of non-small-cell lung cancer: From bench to bedside.

Hu Q, Ma H, Chen H, Zhang Z, Xue Q Cell Death Discov. 2022; 8(1):359.

PMID: 35963868 PMC: 9376075. DOI: 10.1038/s41420-022-01157-4.

References

Pascal L, Oudes A, Petersen T, Goo Y, Walashek L, True L . Molecular and cellular characterization of ABCG2 in the prostate. BMC Urol. 2007; 7:6. PMC: 1853103. DOI: 10.1186/1471-2490-7-6. View

Park I, Zhao R, West J, Yabuuchi A, Huo H, Ince T . Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2007; 451(7175):141-6. DOI: 10.1038/nature06534. View

Wang J . Evaluating therapeutic efficacy against cancer stem cells: new challenges posed by a new paradigm. Cell Stem Cell. 2008; 1(5):497-501. DOI: 10.1016/j.stem.2007.10.005. View

Ma S, Chan K, Hu L, Lee T, Wo J, Ng I . Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology. 2007; 132(7):2542-56. DOI: 10.1053/j.gastro.2007.04.025. View

Chiou S, Wang M, Chou Y, Chen C, Hong C, Hsieh W . Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation. Cancer Res. 2010; 70(24):10433-44. DOI: 10.1158/0008-5472.CAN-10-2638. View

Seigel G, Hackam A, Ganguly A, Mandell L, Gonzalez-Fernandez F . Human embryonic and neuronal stem cell markers in retinoblastoma. Mol Vis. 2007; 13:823-32. PMC: 2768758. View

Costi M, Ferrari S . Update on antifolate drugs targets. Curr Drug Targets. 2001; 2(2):135-66. DOI: 10.2174/1389450013348669. View

Okita K, Ichisaka T, Yamanaka S . Generation of germline-competent induced pluripotent stem cells. Nature. 2007; 448(7151):313-7. DOI: 10.1038/nature05934. View

Pan G, Thomson J . Nanog and transcriptional networks in embryonic stem cell pluripotency. Cell Res. 2007; 17(1):42-9. DOI: 10.1038/sj.cr.7310125. View

10.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

11.

Ibrahim E, Babaei-Jadidi R, Saadeddin A, Spencer-Dene B, Hossaini S, Abuzinadah M . Embryonic NANOG activity defines colorectal cancer stem cells and modulates through AP1- and TCF-dependent mechanisms. Stem Cells. 2012; 30(10):2076-87. DOI: 10.1002/stem.1182. View

12.

Freberg C, Dahl J, Timoskainen S, Collas P . Epigenetic reprogramming of OCT4 and NANOG regulatory regions by embryonal carcinoma cell extract. Mol Biol Cell. 2007; 18(5):1543-53. PMC: 1855029. DOI: 10.1091/mbc.e07-01-0029. View

13.

Di Fiore R, Santulli A, Ferrante R, Giuliano M, De Blasio A, Messina C . Identification and expansion of human osteosarcoma-cancer-stem cells by long-term 3-aminobenzamide treatment. J Cell Physiol. 2009; 219(2):301-13. DOI: 10.1002/jcp.21667. View

14.

Scotlandi K, Serra M, Manara M, Lollini P, Maurici D, Del Bufalo D . Pre-treatment of human osteosarcoma cells with N-methylformamide enhances P-glycoprotein expression and resistance to doxorubicin. Int J Cancer. 1994; 58(1):95-101. DOI: 10.1002/ijc.2910580116. View

15.

Santagata S, Ligon K, Hornick J . Embryonic stem cell transcription factor signatures in the diagnosis of primary and metastatic germ cell tumors. Am J Surg Pathol. 2007; 31(6):836-45. DOI: 10.1097/PAS.0b013e31802e708a. View

16.

Gidekel S, Pizov G, Bergman Y, Pikarsky E . Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell. 2003; 4(5):361-70. DOI: 10.1016/s1535-6108(03)00270-8. View

17.

Fan Y, Zheng M, Tang Y, Liang X . A new perspective of vasculogenic mimicry: EMT and cancer stem cells (Review). Oncol Lett. 2013; 6(5):1174-1180. PMC: 3813799. DOI: 10.3892/ol.2013.1555. View

18.

Zhang J, Espinoza L, Kinders R, Lawrence S, Pfister T, Zhou M . NANOG modulates stemness in human colorectal cancer. Oncogene. 2012; 32(37):4397-405. PMC: 3556342. DOI: 10.1038/onc.2012.461. View

19.

Serra M, Scotlandi K, Manara M, Maurici D, Lollini P, De Giovanni C . Establishment and characterization of multidrug-resistant human osteosarcoma cell lines. Anticancer Res. 1993; 13(2):323-9. View

20.

Trosko J . From adult stem cells to cancer stem cells: Oct-4 Gene, cell-cell communication, and hormones during tumor promotion. Ann N Y Acad Sci. 2007; 1089:36-58. DOI: 10.1196/annals.1386.018. View