Open Access

Antitumor agent 25-epi Ritterostatin GN1N induces endoplasmic reticulum stress and autophagy mediated cell death in melanoma cells

  • Authors:
    • Kausar Begam Riaz Ahmed
    • Ananda Kumar Kanduluru
    • Li Feng
    • Philip L. Fuchs
    • Peng Huang
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  • Published online on: April 3, 2017     https://doi.org/10.3892/ijo.2017.3944
  • Pages: 1482-1490
  • Copyright: © Riaz Ahmed et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Metastatic melanoma is the most aggressive of all skin cancers and is associated with poor prognosis owing to lack of effective treatments. 25-epi Ritterostatin GN1N is a novel antitumor agent with yet undefined mechanisms of action. We sought to delineate the antitumor mechanisms of 25-epi Ritterostatin GN1N in melanoma cells to determine the potential of this compound as a treatment for melanoma. Activation of the endoplasmic reticulum (ER) stress protein glucose-regulated protein 78 (GRP78) has been associated with increased melanoma progression, oncogenic signaling, drug resistance, and suppression of cell death. We found that 25-epi Ritterostatin GN1N induced cell death in melanoma cells at nanomolar concentrations, and this cell death was characterized by inhibition of GRP78 expression, increased expression of the ER stress marker CHOP, loss of mitochondrial membrane potential, and lipidation of the autophagy marker protein LC3B. Importantly, normal melanocytes exhibited limited sensitivity to 25-epi Ritterostatin GN1N. Subsequent in vivo results demonstrated that 25-epi Ritterostatin GN1N reduced melanoma growth in mouse tumor xenografts and did not affect body weight, suggesting minimal toxicity. In summary, our findings indicate that 25-epi Ritterostatin GN1N causes ER stress and massive autophagy, leading to collapse of mitochondrial membrane potential and cell death in melanoma cells, with minimal effects in normal melanocytes. Thus, 25-epi Ritterostatin GN1N is a promising anticancer agent that warrants further investigation.
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May-2017
Volume 50 Issue 5

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

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Spandidos Publications style
Riaz Ahmed KB, Kanduluru AK, Feng L, Fuchs PL and Huang P: Antitumor agent 25-epi Ritterostatin GN1N induces endoplasmic reticulum stress and autophagy mediated cell death in melanoma cells. Int J Oncol 50: 1482-1490, 2017
APA
Riaz Ahmed, K.B., Kanduluru, A.K., Feng, L., Fuchs, P.L., & Huang, P. (2017). Antitumor agent 25-epi Ritterostatin GN1N induces endoplasmic reticulum stress and autophagy mediated cell death in melanoma cells. International Journal of Oncology, 50, 1482-1490. https://doi.org/10.3892/ijo.2017.3944
MLA
Riaz Ahmed, K. B., Kanduluru, A. K., Feng, L., Fuchs, P. L., Huang, P."Antitumor agent 25-epi Ritterostatin GN1N induces endoplasmic reticulum stress and autophagy mediated cell death in melanoma cells". International Journal of Oncology 50.5 (2017): 1482-1490.
Chicago
Riaz Ahmed, K. B., Kanduluru, A. K., Feng, L., Fuchs, P. L., Huang, P."Antitumor agent 25-epi Ritterostatin GN1N induces endoplasmic reticulum stress and autophagy mediated cell death in melanoma cells". International Journal of Oncology 50, no. 5 (2017): 1482-1490. https://doi.org/10.3892/ijo.2017.3944