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Rapamycin inhibited the function of lung CSCs via SOX2

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Tumor Biology

Abstract

The presence of cancer stem cells (CSCs) is the source of occurrence, aggravation, and recurrence of lung cancer. Accordingly, targeting killing the lung CSCs has been suggested to be an effective approach for lung cancer treatment. In this study, we showed that rapamycin inhibited the mammalian target of rapamycin (mTOR) signal transduction in A549 cells and improved the sensitivity to cisplatin (DDP). The mechanisms involve inhibition of the SOX2 expression, cell proliferation, epithelial-mesenchymal transition (EMT) phenotype, and sphere formation. Interestingly, knocked down SOX2 was a similar effect with rapamycin in A549 sphere. Furthermore, we showed that ectopic expression of Sox2 in A549 cells was sufficient to render them more resistant to rapamycin treatment in vitro. These data suggested that rapamycin inhibited the function of lung CSCs via SOX2. It will be of great interest to further explore the therapeutic strategies of lung cancer.

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References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62:220–41.

    Article  PubMed  Google Scholar 

  3. Chen DQ, Huang JY, Feng B, Pan BZ, De W, Wang R, et al. Histone deacetylase 1/sp1/microrna-200b signaling accounts for maintenance of cancer stem-like cells in human lung adenocarcinoma. PLoS One. 2014;9:e109578.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ye XQ, Li Q, Wang GH, Sun FF, Huang GJ, Bian XW, et al. Mitochondrial and energy metabolism-related properties as novel indicators of lung cancer stem cells. Int J Cancer J Int Cancer. 2011;129:820–31.

    Article  CAS  Google Scholar 

  5. Bergamaschi A, Madak-Erdogan Z, Kim YJ, Choi YL, Lu H, Katzenellenbogen BS. The forkhead transcription factor foxm1 promotes endocrine resistance and invasiveness in estrogen receptor-positive breast cancer by expansion of stem-like cancer cells. Breast Cancer Res BCR. 2014;16:436.

    Article  PubMed  Google Scholar 

  6. Chai S, Tong M, Ng KY, Kwan PS, Chan YP, Fung TM, et al. Regulatory role of mir-142-3p on the functional hepatic cancer stem cell marker cd133. Oncotarget. 2014;5:5725–35.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8:755–68.

    Article  CAS  PubMed  Google Scholar 

  8. Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, Garcia-Echeverria C, et al. The role of pten/akt/pi3k signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci U S A. 2009;106:268–73.

    Article  CAS  PubMed  Google Scholar 

  9. Kornakiewicz A, Solarek W, Bielecka ZF, Lian F, Szczylik C, Czarnecka AM. Mammalian target of rapamycin inhibitors resistance mechanisms in clear cell renal cell carcinoma. Curr Signal Transduct Ther. 2014;8:210–8.

    Article  PubMed  Google Scholar 

  10. Laplante M, Sabatini DM. Mtor signaling in growth control and disease. Cell. 2012;149:274–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Marinov M, Fischer B, Arcaro A. Targeting mtor signaling in lung cancer. Crit Rev Oncol Hematol. 2007;63:172–82.

    Article  PubMed  Google Scholar 

  12. Zhou J, Wulfkuhle J, Zhang H, Gu P, Yang Y, Deng J, et al. Activation of the pten/mtor/stat3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci U S A. 2007;104:16158–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fang DD, Zhang CC, Gu Y, Jani JP, Cao J, Tsaparikos K, et al. Antitumor efficacy of the dual pi3k/mtor inhibitor pf-04691502 in a human xenograft tumor model derived from colorectal cancer stem cells harboring a mutation. PLoS One. 2013;8:e67258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kahn J, Hayman TJ, Jamal M, Rath BH, Kramp T, Camphausen K, et al. The mtorc1/mtorc2 inhibitor azd2014 enhances the radiosensitivity of glioblastoma stem-like cells. Neuro-Oncology. 2014;16:29–37.

    Article  CAS  PubMed  Google Scholar 

  15. Dong P, Konno Y, Watari H, Hosaka M, Noguchi M, Sakuragi N. The impact of microrna-mediated pi3k/akt signaling on epithelial-mesenchymal transition and cancer stemness in endometrial cancer. J Transl Med. 2014;12:231.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Bass AJ, Watanabe H, Mermel CH, Yu S, Perner S, Verhaak RG, et al. Sox2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet. 2009;41:1238–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sun FF, Hu YH, Xiong LP, Tu XY, Zhao JH, Chen SS, et al. Enhanced expression of stem cell markers and drug resistance in sphere-forming non-small cell lung cancer cells. Int J Clin Exp Pathol. 2015;8:6287–300.

    PubMed  PubMed Central  Google Scholar 

  18. Yin S, Wang P, Deng W, Zheng H, Hu L, Hurst LD, et al. Dosage compensation on the active x chromosome minimizes transcriptional noise of x-linked genes in mammals. Genome Biol. 2009;10:R74.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Matsubara S, Ding Q, Miyazaki Y, Kuwahata T, Tsukasa K, Takao S. Mtor plays critical roles in pancreatic cancer stem cells through specific and stemness-related functions. Sci Rep. 2013;3:3230.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011;17:313–9.

    Article  CAS  PubMed  Google Scholar 

  21. Gangemi R, Paleari L, Orengo AM, Cesario A, Chessa L, Ferrini S, et al. Cancer stem cells: a new paradigm for understanding tumor growth and progression and drug resistance. Curr Med Chem. 2009;16:1688–703.

    Article  CAS  PubMed  Google Scholar 

  22. Rycaj K, Tang DG. Cancer stem cells and radioresistance. Int J Radiat Biol. 2014;90:615–21.

    Article  CAS  PubMed  Google Scholar 

  23. Chan CT, Pang YL, Deng W, Babu IR, Dyavaiah M, Begley TJ, et al. Reprogramming of trna modifications controls the oxidative stress response by codon-biased translation of proteins. Nat Commun. 2012;3:937.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Xiao Z, Sperl B, Ullrich A, Knyazev P. Metformin and salinomycin as the best combination for the eradication of nsclc monolayer cells and their alveospheres (cancer stem cells) irrespective of egfr, kras, eml4/alk and lkb1 status. Oncotarget. 2014;5:12877–90.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Gaur P, Sceusi EL, Samuel S, Xia L, Fan F, Zhou Y, et al. Identification of cancer stem cells in human gastrointestinal carcinoid and neuroendocrine tumors. Gastroenterology. 2011;141:1728–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mueller MT, Hermann PC, Witthauer J, Rubio-Viqueira B, Leicht SF, Huber S, et al. Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer. Gastroenterology. 2009;137:1102–13.

    Article  CAS  PubMed  Google Scholar 

  27. Gulhati P, Cai Q, Li J, Liu J, Rychahou PG, Qiu S, et al. Targeted inhibition of mammalian target of rapamycin signaling inhibits tumorigenesis of colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2009;15:7207–16.

    Article  CAS  Google Scholar 

  28. Yin S, Yang J, Lin B, Deng W, Zhang Y, Yi X, et al. Exome sequencing identifies frequent mutation of mll2 in non-small cell lung carcinoma from chinese patients. Sci Rep. 2014;4:6036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dean M. Abc transporters, drug resistance, and cancer stem cells. J Mammary Gland Biol Neoplasia. 2009;14:3–9.

    Article  PubMed  Google Scholar 

  30. Moitra K, Lou H, Dean M. Multidrug efflux pumps and cancer stem cells: insights into multidrug resistance and therapeutic development. Clin Pharmacol Ther. 2011;89:491–502.

    Article  CAS  PubMed  Google Scholar 

  31. Elliott A, Adams J, Al-Hajj M. The abcs of cancer stem cell drug resistance. IDrugs Investig Drugs J. 2010;13:632–5.

    CAS  Google Scholar 

  32. Deng WJ, Nie S, Dai J, Wu JR, Zeng R. Proteome, phosphoproteome, and hydroxyproteome of liver mitochondria in diabetic rats at early pathogenic stages. Mol Cell Proteomics MCP. 2010;9:100–16.

    Article  CAS  PubMed  Google Scholar 

  33. Yin S, Deng W, Zheng H, Zhang Z, Hu L, Kong X. Evidence that the nonsense-mediated mrna decay pathway participates in x chromosome dosage compensation in mammals. Biochem Biophys Res Commun. 2009;383:378–82.

    Article  CAS  PubMed  Google Scholar 

  34. Yin S, Deng W, Hu L, Kong X. The impact of nucleosome positioning on the organization of replication origins in eukaryotes. Biochem Biophys Res Commun. 2009;385:363–8.

    Article  CAS  PubMed  Google Scholar 

  35. Fuchs D, Daniel V, Sadeghi M, Opelz G, Naujokat C. Salinomycin overcomes abc transporter-mediated multidrug and apoptosis resistance in human leukemia stem cell-like kg-1a cells. Biochem Biophys Res Commun. 2010;394:1098–104.

    Article  CAS  PubMed  Google Scholar 

  36. Yang C, Zhang Y, Zhang Y, Zhang Z, Peng J, Li Z, Han L, You Q, Chen X, Rao X, Zhu Y, Liao Z. Downregulation of cancer stem cell properties via mtor signaling pathway inhibition by rapamycin in nasopharyngeal carcinoma. Int J Oncol. 2015.

  37. Engelman JA. Targeting pi3k signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9:550–62.

    Article  CAS  PubMed  Google Scholar 

  38. Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR. Mammalian target of rapamycin is a direct target for protein kinase b: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J. 1999;344(Pt 2):427–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zou M, Hu C, You Q, Zhang A, Wang X, Guo Q. Oroxylin a induces autophagy in human malignant glioma cells via the mtor-stat3-notch signaling pathway. Mol Carcinog. 2014.

  40. Pastrana E, Silva-Vargas V, Doetsch F. Eyes wide open: a critical review of sphere-formation as an assay for stem cells. Cell Stem Cell. 2011;8:486–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.

    Article  CAS  PubMed  Google Scholar 

  42. Chan CT, Deng W, Li F, DeMott MS, Babu IR, Begley TJ, et al. Highly predictive reprogramming of trna modifications is linked to selective expression of codon-biased genes. Chem Res Toxicol. 2015;28:978–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pirozzi G, Tirino V, Camerlingo R, Franco R, La Rocca A, Liguori E, et al. Epithelial to mesenchymal transition by tgfbeta-1 induction increases stemness characteristics in primary non small cell lung cancer cell line. PLoS One. 2011;6:e21548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Saxena M, Stephens MA, Pathak H, Rangarajan A. Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating abc transporters. Cell Death Dis. 2011;2:e179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Boumahdi S, Driessens G, Lapouge G, Rorive S, Nassar D, Le Mercier M, et al. Sox2 controls tumour initiation and cancer stem-cell functions in squamous-cell carcinoma. Nature. 2014;511:246–50.

    Article  CAS  PubMed  Google Scholar 

  47. Hagerstrand D, He X, Bradic Lindh M, Hoefs S, Hesselager G, Ostman A, et al. Identification of a sox2-dependent subset of tumor- and sphere-forming glioblastoma cells with a distinct tyrosine kinase inhibitor sensitivity profile. Neuro-Oncology. 2011;13:1178–91.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Yang N, Hui L, Wang Y, Yang H, Jiang X. Overexpression of sox2 promotes migration, invasion, and epithelial-mesenchymal transition through the wnt/beta-catenin pathway in laryngeal cancer hep-2 cells. Tumour Biol J Int Soc Oncodevelop Biol Med. 2014;35:7965–73.

    Article  CAS  Google Scholar 

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Acknowledgments

This program is supported by National Science Foundation of China (NSFC, 81160277) to X. Ye.

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Correspondence to Xiao-Qun Ye.

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Li-Xia Xie and Feng-Feng Sun contributed equally to this work.

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Xie, LX., Sun, FF., He, BF. et al. Rapamycin inhibited the function of lung CSCs via SOX2. Tumor Biol. 37, 4929–4937 (2016). https://doi.org/10.1007/s13277-015-4341-y

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  • DOI: https://doi.org/10.1007/s13277-015-4341-y

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