Transient activation of EGFR/AKT cell survival pathway and expression of survivin contribute to reduced sensitivity of human melanoma cells to betulinic acid

  • Authors:
    • Lihua Qiu
    • Qun Wang
    • Wen Di
    • Qin Jiang
    • Erica Schefeller
    • Steve Derby
    • Harold Wanebo
    • Bingfang Yan
    • Yinsheng Wan
  • View Affiliations

  • Published online on: September 1, 2005     https://doi.org/10.3892/ijo.27.3.823
  • Pages: 823-830
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Abstract

Betulinic acid (BA), a pentacyclic triterpene first identified less than a decade ago, has served as a melanoma-specific cytotoxic agent, and yet its specificity is being challenged. Recently, we found that human melanoma cells exhibited less sensitivity to betulinic acid than human skin keratinocytes. This study was designed to investigate the cell signaling pathway leading human melanoma cells to increased resistance to betulinic acid treatment. In vitro experiments using cultured human melanoma cells indicated that betulinic acid transiently induced survivin expression. The expression of survivin started 30 min post-betulinic acid treatment, peaked at 2 h, remained elevated for 8 h and returned to basal level within 24 h. Similarly, epithelial growth factor (EGF) treatment induced expression of survivin in a time-dependent manner. Since epithelial growth factor receptor (EGFR) activation leads to the activation of cell signaling components that are important to cell survival, we next examined whether BA-induced survivin expression is mediated by the EGFR pathway. The results showed that BA induced EGFR tyrosine phosphorylation in a time-dependent manner. Further, BA strongly induced AKT phosphorylation in a similar pattern. AKT activation started 15 min post-treatment, peaked at approximately 1 h, remained elevated for 4 h and returned to basal level within 8 h. BA also induced ERK activation and, in contrast, weakly induced JNK and p38 activation. Pretreatment of EGFR inhibitor PD153035 blocked BA-induced EGFR phosphorylation, ERK and AKT activation, and survivin expression. Results of the MTT dye assay showed that a combination of PD153035 and BA enhanced melanoma cell death. Collectively, we conclude that betulinic acid transiently activated the EGFR/AKT cell survival pathway and induced survivin expression, contributing to less sensitivity in human melanoma cells. The data suggest that a combination of the EGFR inhibitor and betulinic acid may be a better clinical option to treat human melanoma.
Journal Cover

September 2005
Volume 27 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Qiu L, Wang Q, Di W, Jiang Q, Schefeller E, Derby S, Wanebo H, Yan B and Wan Y: Transient activation of EGFR/AKT cell survival pathway and expression of survivin contribute to reduced sensitivity of human melanoma cells to betulinic acid. Int J Oncol 27: 823-830, 2005.
APA
Qiu, L., Wang, Q., Di, W., Jiang, Q., Schefeller, E., Derby, S. ... Wan, Y. (2005). Transient activation of EGFR/AKT cell survival pathway and expression of survivin contribute to reduced sensitivity of human melanoma cells to betulinic acid. International Journal of Oncology, 27, 823-830. https://doi.org/10.3892/ijo.27.3.823
MLA
Qiu, L., Wang, Q., Di, W., Jiang, Q., Schefeller, E., Derby, S., Wanebo, H., Yan, B., Wan, Y."Transient activation of EGFR/AKT cell survival pathway and expression of survivin contribute to reduced sensitivity of human melanoma cells to betulinic acid". International Journal of Oncology 27.3 (2005): 823-830.
Chicago
Qiu, L., Wang, Q., Di, W., Jiang, Q., Schefeller, E., Derby, S., Wanebo, H., Yan, B., Wan, Y."Transient activation of EGFR/AKT cell survival pathway and expression of survivin contribute to reduced sensitivity of human melanoma cells to betulinic acid". International Journal of Oncology 27, no. 3 (2005): 823-830. https://doi.org/10.3892/ijo.27.3.823
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