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Article

Hypoxia increases the heterogeneity of melanoma cell populations and affects the response to vemurafenib

  • Authors:
    • Daniela Pucciarelli
    • Nina Lengger
    • Martina Takáčová
    • Lucia Csaderova
    • Maria Bartosova
    • Heimo Breiteneder
    • Silvia Pastorekova
    • Christine Hafner
  • View Affiliations / Copyright

    Affiliations: Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna A‑1090, Austria, Institute of Virology, Department of Molecular Medicine, Slovak Academy of Sciences, Bratislava 81101, Slovakia
  • Pages: 3281-3288
    |
    Published online on: February 10, 2016
       https://doi.org/10.3892/mmr.2016.4888
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Abstract

A hypoxic microenvironment is one of the predominant reasons for incomplete response to melanoma treatment. Vemurafenib, which targets the mutated BRAF-V600 kinase, improves melanoma patient survival, however, resistance invariably develops. The present study evaluated the effect of hypoxia on three BRAF-V600E mutant melanoma cell lines, M14, A375 and 518A2, treated with vemurafenib. Compared with the other two cell lines, hypoxic vemurafenib-treated A375 cells exhibited an enhanced cell proliferation rate and migratory capacity compared with normoxic vemurafenib-treated A375 cells. Immunoblotting analyses revealed that the expression levels of hypoxia inducible factor (HIF)1α and carbonic anhydrase IX were reduced in vemurafenib‑treated M14 and 518A2 cells, however, not in A375 cells. The expression levels of the mitogen‑activated protein kinase, Janus kinase-signal transducer and activator of transcription, and phosphatidylinositol-4,5-bisphosphate 3‑kinase signaling pathway proteins revealed a cell‑type specific response to vemurafenib and hypoxia. Knockdown experiments of HIF1α performed in hypoxic A375 cells decreased the expression of phosphorylated (p‑)protein kinase B, which was restored following vemurafenib treatment, and increased the expression of p‑extracellular‑signal‑regulated kinases. Therefore, three melanoma cell lines responded to vemurafenib under hypoxia in a cell type‑specific manner, suggesting that a subset of cells provides a treatment-resistant pool, from which disease relapse may originate. These data confirmed that vemurafenib may be successful in treating the proliferating cells, whereas the non‑proliferating subpopulation must be addressed by a combination of vemurafenib with other treatment strategies.
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1 

Rohwer N and Cramer T: Hypoxia-mediated drug resistance: Novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Update. 14:191–201. 2011. View Article : Google Scholar

2 

Pastorek J and Pastorekova S: Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy: From biology to clinical use. Semin Cancer Biol. 31:52–64. 2015. View Article : Google Scholar

3 

Hanna SC, Krishnan B, Bailey ST, Moschos SJ, Kuan PF, Shimamura T, Osborne LD, Siegel MB, Duncan LM, O'Brien ET III, et al: HIF1 alpha and HIF2α independently activate SRC to promote melanoma metastases. J Clin Invest. 123:2078–2093. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Semenza GL: Hypoxia-inducible factors: Mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 33:207–214. 2012. View Article : Google Scholar : PubMed/NCBI

5 

Ivanov S, Liao SY, Ivanova A, Danilkovitch-Miagkova A, Tarasova N, Weirich G, Merrill MJ, Proescholdt MA, Oldfield EH, Lee J, et al: Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol. 158:905–919. 2001. View Article : Google Scholar : PubMed/NCBI

6 

Chrastina A, Závada J, Parkkila S, Kaluz T, Kaluzová M, Rajcáni J, Patorek J and Pastoreková S: Biodistribution and pharmacokinetics of I-125I-labeled monoclonal antibody M75 specific for carbonic anhydrase IX, an intrinsic marker of hypoxia, in nude mice xenografted with human colorectal carcinoma. Int J Cancer. 105:873–881. 2003. View Article : Google Scholar : PubMed/NCBI

7 

Syrjänen L, Luukkaala T, Leppilampi M, Kallioinen M, Pastorekova S, Pastorek J, Waheed A, Sly WS, Parkkila S and Karttunen T: Expression of cancer-related carbonic anhydrases IX and XII in normal skin and skin neoplasms. APMIS. 122:880–889. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Kumar SM, Yu H, Edwards R, Chen L, Kazianis S, Brafford P, Acs G, Herlyn M and Xu XW: Mutant V600E BRAF increases hypoxia inducible factor-1alpha expression in melanoma. Cancer Res. 67:3177–3184. 2007. View Article : Google Scholar : PubMed/NCBI

9 

Halaban R, Zhang W, Bacchiocchi A, Cheng E, Parisi F, Ariyan S, Krauthammer M, McCusker JP, Kluger Y and Sznol M: PLX4032, a selective BRAF (V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF (WT) melanoma cells. Pigm Cell Melanoma Res. 23:190–200. 2010. View Article : Google Scholar

10 

Botton T, Yeh I, Nelson T, Vemula SS, Sparatta A, Garrido MC, Allegra M, Rocchi S, Bahadoran P, McCalmont TH, et al: Recurrent BRAF kinase fusions in melanocytic tumors offer an opportunity for targeted therapy. Pigment Cell Melanoma Res. 26:845–851. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Azijli K, Stelloo E, Peters GJ and VAN DEN Eertwegh AJ: New developments in the treatment of metastatic melanoma: Immune checkpoint inhibitors and targeted therapies. Anticancer Res. 34:1493–1505. 2014.PubMed/NCBI

12 

Lee JT, Li L, Brafford PA, van den Eijnden M, Halloran MB, Sproesser K, Haass NK, Smalley KS, Tsai J, Bollag G and Herlyn M: PLX4032, a potent inhibitor of the B-Raf V600E oncogene, selectively inhibits V600E-positive melanomas. Pigment Cell Melanoma Res. 23:820–827. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, et al: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 364:2507–2516. 2011. View Article : Google Scholar : PubMed/NCBI

14 

Wagenaar TR, Ma LY, Roscoe B, Park SM, Bolon DN and Green MR: Resistance to vemurafenib resulting from a novel mutation in the BRAFV600E kinase domain. Pigm Cell Melanoma Res. 27:124–133. 2014. View Article : Google Scholar

15 

O'Connell MP, Marchbank K, Webster MR, Valiga AA, Kaur A, Vultur A, Li L, Herlyn M, Villanueva J, Liu Q, et al: Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2. Cancer Discov. 3:1378–1393. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Wagner S, Hafner C, Allwardt D, Jasinska J, Ferrone S, Zielinski CC, Scheiner O, Wiedermann U, Pehamberger H and Breiteneder H: Vaccination with a human high molecular weight melanoma-associated antigen mimotope induces a humoral response inhibiting melanoma cell growth in vitro. J Immunol. 174:976–982. 2005. View Article : Google Scholar : PubMed/NCBI

17 

Pastoreková S, Závadová Z, Kostál M, Babusíková O and Závada J: A novel quasi-viral agent, Ma Tu, is a 2-component system. Virology. 187:620–626. 1992. View Article : Google Scholar

18 

Svastova E, Witarski W, Csaderova L, Kosik I, Skvarkova L, Hulikova A, Zatovicova M, Barathova M, Kopacek J, Pastorek J and Pastorekova S: Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain. J Biol Chem. 287:3392–3402. 2012. View Article : Google Scholar :

19 

Schneider CA, Rasband WS and Eliceiri KW: NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 9:671–5. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Widmer DS, Hoek KS, Cheng PF, Eichhoff OM, Biedermann T, Raaijmakers MI, Hemmi S, Dunnmer R and Levesque MP: Hypoxia contributes to melanoma heterogeneity by triggering HIF1α-dependent phenotype switching. J Invest Dermatol. 133:2436–2443. 2013. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Pucciarelli D, Lengger N, Takáčová M, Csaderova L, Bartosova M, Breiteneder H, Pastorekova S and Hafner C: Hypoxia increases the heterogeneity of melanoma cell populations and affects the response to vemurafenib. Mol Med Rep 13: 3281-3288, 2016.
APA
Pucciarelli, D., Lengger, N., Takáčová, M., Csaderova, L., Bartosova, M., Breiteneder, H. ... Hafner, C. (2016). Hypoxia increases the heterogeneity of melanoma cell populations and affects the response to vemurafenib. Molecular Medicine Reports, 13, 3281-3288. https://doi.org/10.3892/mmr.2016.4888
MLA
Pucciarelli, D., Lengger, N., Takáčová, M., Csaderova, L., Bartosova, M., Breiteneder, H., Pastorekova, S., Hafner, C."Hypoxia increases the heterogeneity of melanoma cell populations and affects the response to vemurafenib". Molecular Medicine Reports 13.4 (2016): 3281-3288.
Chicago
Pucciarelli, D., Lengger, N., Takáčová, M., Csaderova, L., Bartosova, M., Breiteneder, H., Pastorekova, S., Hafner, C."Hypoxia increases the heterogeneity of melanoma cell populations and affects the response to vemurafenib". Molecular Medicine Reports 13, no. 4 (2016): 3281-3288. https://doi.org/10.3892/mmr.2016.4888
Copy and paste a formatted citation
x
Spandidos Publications style
Pucciarelli D, Lengger N, Takáčová M, Csaderova L, Bartosova M, Breiteneder H, Pastorekova S and Hafner C: Hypoxia increases the heterogeneity of melanoma cell populations and affects the response to vemurafenib. Mol Med Rep 13: 3281-3288, 2016.
APA
Pucciarelli, D., Lengger, N., Takáčová, M., Csaderova, L., Bartosova, M., Breiteneder, H. ... Hafner, C. (2016). Hypoxia increases the heterogeneity of melanoma cell populations and affects the response to vemurafenib. Molecular Medicine Reports, 13, 3281-3288. https://doi.org/10.3892/mmr.2016.4888
MLA
Pucciarelli, D., Lengger, N., Takáčová, M., Csaderova, L., Bartosova, M., Breiteneder, H., Pastorekova, S., Hafner, C."Hypoxia increases the heterogeneity of melanoma cell populations and affects the response to vemurafenib". Molecular Medicine Reports 13.4 (2016): 3281-3288.
Chicago
Pucciarelli, D., Lengger, N., Takáčová, M., Csaderova, L., Bartosova, M., Breiteneder, H., Pastorekova, S., Hafner, C."Hypoxia increases the heterogeneity of melanoma cell populations and affects the response to vemurafenib". Molecular Medicine Reports 13, no. 4 (2016): 3281-3288. https://doi.org/10.3892/mmr.2016.4888
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