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Differential expression of ABCB5 in BRAF inhibitor-resistant melanoma cell lines.
BMC Cancer. 2018 Jun 22; 18(1):675.BC

Abstract

BACKGROUND

More than 50% of metastatic melanoma patients have a specific mutation in the serine/threonine kinase BRAF. This results in constitutive activation of the RAS-RAF-MEK-ERK-MAP kinase pathway, which causes uncontrolled cell growth. Vemurafenib (PLX4032) is an oral chemotherapeutic agent that targets the specific mutation V600E in the BRAF protein. Initial response rates are high in patients with BRAF mutant melanoma treated with a BRAF inhibitor such as vemurafenib, but resistance nearly always develops and disease progression ensues. There are several different mechanisms by which melanoma develops BRAF inhibitor resistance. One potential component of resistance is increased drug efflux. Overexpressed ABCB5 (ATP-binding cassette transporter, subfamily B, member 5) has been shown to efflux anti-cancer drugs from cancer cells. The purpose of this study is to determine whether ABCB5 is highly expressed in BRAF inhibitor-resistant melanoma cells and to evaluate whether ABCB5 is involved in the development of resistance to BRAF inhibitors in cutaneous melanoma.

METHODS

We established three BRAF inhibitor-resistant melanoma cell lines with BRAF mutation. The expression level of ABCB5 in PLX-resistant cell lines was checked by real-time PCR and Western blot analysis. SK-MEL-2 melanoma cells with wild-type BRAF were used for comparison. The association of different levels of ABCB5 with the changes of ERK, p-ERK, Akt and p-Akt was also assessed by Western blotting. Re-sensitization of melanoma cells to PLX was tested by p-ERK inhibitor PD58059 and ABCB5 knockdown by ABCB5 siRNA, respectively.

RESULTS

We showed that ABCB5 was overexpressed in SK-MEL-28PLXr and A2058PLXr cells but not in A375PLXr cells. ABCB5 overexpression is associated with activation of p-ERK status but not Akt. Inhibition of p-ERK re-sensitized SK-MEL-28PLXr and A2058PLXr cells to PLX treatment, but knockdown of ABCB5 did not re-sensitize A2058 PLXr and SK-MEL-28 PLXr cells to PLX treatment.

CONCLUSION

These results confirm that, even though ABCB5 was overexpressed in SK-MEL-28 and A2058 melanoma cells that develop resistance to BRAF inhibitors, ABCB5 may not be a major targetable contributor to BRAF resistance. p-ERK inhibition may play important roles in BRAF resistance in these two melanoma cell lines.

Authors+Show Affiliations

The Hiram C. Polk, Jr MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA.The Hiram C. Polk, Jr MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA.The Hiram C. Polk, Jr MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA.The Hiram C. Polk, Jr MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA. h0hao001@louisville.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29929490

Citation

Xiao, Jingjing, et al. "Differential Expression of ABCB5 in BRAF Inhibitor-resistant Melanoma Cell Lines." BMC Cancer, vol. 18, no. 1, 2018, p. 675.
Xiao J, Egger ME, McMasters KM, et al. Differential expression of ABCB5 in BRAF inhibitor-resistant melanoma cell lines. BMC Cancer. 2018;18(1):675.
Xiao, J., Egger, M. E., McMasters, K. M., & Hao, H. (2018). Differential expression of ABCB5 in BRAF inhibitor-resistant melanoma cell lines. BMC Cancer, 18(1), 675. https://doi.org/10.1186/s12885-018-4583-3
Xiao J, et al. Differential Expression of ABCB5 in BRAF Inhibitor-resistant Melanoma Cell Lines. BMC Cancer. 2018 Jun 22;18(1):675. PubMed PMID: 29929490.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential expression of ABCB5 in BRAF inhibitor-resistant melanoma cell lines. AU - Xiao,Jingjing, AU - Egger,Michael E, AU - McMasters,Kelly M, AU - Hao,Hongying, Y1 - 2018/06/22/ PY - 2017/10/30/received PY - 2018/06/12/accepted PY - 2018/6/23/entrez PY - 2018/6/23/pubmed PY - 2019/2/9/medline KW - ATP-binding cassette transporter 5 (ABCB5) KW - BRAF melanoma KW - Chemoresistance KW - Vemurafenib (PLX4032) SP - 675 EP - 675 JF - BMC cancer JO - BMC Cancer VL - 18 IS - 1 N2 - BACKGROUND: More than 50% of metastatic melanoma patients have a specific mutation in the serine/threonine kinase BRAF. This results in constitutive activation of the RAS-RAF-MEK-ERK-MAP kinase pathway, which causes uncontrolled cell growth. Vemurafenib (PLX4032) is an oral chemotherapeutic agent that targets the specific mutation V600E in the BRAF protein. Initial response rates are high in patients with BRAF mutant melanoma treated with a BRAF inhibitor such as vemurafenib, but resistance nearly always develops and disease progression ensues. There are several different mechanisms by which melanoma develops BRAF inhibitor resistance. One potential component of resistance is increased drug efflux. Overexpressed ABCB5 (ATP-binding cassette transporter, subfamily B, member 5) has been shown to efflux anti-cancer drugs from cancer cells. The purpose of this study is to determine whether ABCB5 is highly expressed in BRAF inhibitor-resistant melanoma cells and to evaluate whether ABCB5 is involved in the development of resistance to BRAF inhibitors in cutaneous melanoma. METHODS: We established three BRAF inhibitor-resistant melanoma cell lines with BRAF mutation. The expression level of ABCB5 in PLX-resistant cell lines was checked by real-time PCR and Western blot analysis. SK-MEL-2 melanoma cells with wild-type BRAF were used for comparison. The association of different levels of ABCB5 with the changes of ERK, p-ERK, Akt and p-Akt was also assessed by Western blotting. Re-sensitization of melanoma cells to PLX was tested by p-ERK inhibitor PD58059 and ABCB5 knockdown by ABCB5 siRNA, respectively. RESULTS: We showed that ABCB5 was overexpressed in SK-MEL-28PLXr and A2058PLXr cells but not in A375PLXr cells. ABCB5 overexpression is associated with activation of p-ERK status but not Akt. Inhibition of p-ERK re-sensitized SK-MEL-28PLXr and A2058PLXr cells to PLX treatment, but knockdown of ABCB5 did not re-sensitize A2058 PLXr and SK-MEL-28 PLXr cells to PLX treatment. CONCLUSION: These results confirm that, even though ABCB5 was overexpressed in SK-MEL-28 and A2058 melanoma cells that develop resistance to BRAF inhibitors, ABCB5 may not be a major targetable contributor to BRAF resistance. p-ERK inhibition may play important roles in BRAF resistance in these two melanoma cell lines. SN - 1471-2407 UR - https://www.unboundmedicine.com/medline/citation/29929490/Differential_expression_of_ABCB5_in_BRAF_inhibitor_resistant_melanoma_cell_lines_ L2 - https://bmccancer.biomedcentral.com/articles/10.1186/s12885-018-4583-3 DB - PRIME DP - Unbound Medicine ER -