Open Access

Podophyllotoxin acetate triggers anticancer effects against non-small cell lung cancer cells by promoting cell death via cell cycle arrest, ER stress and autophagy

  • Authors:
    • Jae Yeon Choi
    • Wan Gi Hong
    • Jeong Hyun Cho
    • Eun Mi Kim
    • Jongdoo Kim
    • Chan-Hun Jung
    • Sang-Gu Hwang
    • Hong-Duck Um
    • Jong Kuk Park
  • View Affiliations

  • Published online on: August 13, 2015     https://doi.org/10.3892/ijo.2015.3123
  • Pages: 1257-1265
  • Copyright: © Choi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

We previously reported that podophyllotoxin acetate (PA) radiosensitizes NCI-H460 cells. Here, we confirmed that PA treatment also induces cell death among two other non-small cell lung cancer (NSCLC) cell lines: NCI-H1299 and A549 cells (IC50 values = 7.6 and 16.1 nM, respectively). Our experiments further showed that PA treatment was able to induce cell death via various mechanisms. First, PA dose-dependently induced cell cycle arrest at G2/M phase, as shown by accumulation of the mitosis-related proteins, p21, survivin and Aurora B. This G2/M phase arrest was due to the PA-induced inhibition of microtubule polymerization. Together, the decreased microtubule polymerization and increased cell cycle arrest induced DNA damage (reflected by accumulation of γ-H2AX) and triggered the induction of intrinsic and extrinsic apoptotic pathways, as shown by the time-dependent activations of caspase-3, -8 and -9. Second, PA time-dependently activated the pro-apoptotic ER stress pathway, as evidenced by increased expression levels of BiP, CHOP, IRE1-α, phospho-PERK, and phospho-JNK. Third, PA activated autophagy, as reflected by time-dependent increases in the expression levels of beclin-1, Atg3, Atg5 and Atg7, and the cleavage of LC3. Collectively, these results suggest a model wherein PA decreases microtubule polymerization and increases cell cycle arrest, thereby inducing apoptotic cell death via the activation of DNA damage, ER stress and autophagy.
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October-2015
Volume 47 Issue 4

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

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Spandidos Publications style
Choi JY, Hong WG, Cho JH, Kim EM, Kim J, Jung C, Hwang S, Um H and Park JK: Podophyllotoxin acetate triggers anticancer effects against non-small cell lung cancer cells by promoting cell death via cell cycle arrest, ER stress and autophagy. Int J Oncol 47: 1257-1265, 2015
APA
Choi, J.Y., Hong, W.G., Cho, J.H., Kim, E.M., Kim, J., Jung, C. ... Park, J.K. (2015). Podophyllotoxin acetate triggers anticancer effects against non-small cell lung cancer cells by promoting cell death via cell cycle arrest, ER stress and autophagy. International Journal of Oncology, 47, 1257-1265. https://doi.org/10.3892/ijo.2015.3123
MLA
Choi, J. Y., Hong, W. G., Cho, J. H., Kim, E. M., Kim, J., Jung, C., Hwang, S., Um, H., Park, J. K."Podophyllotoxin acetate triggers anticancer effects against non-small cell lung cancer cells by promoting cell death via cell cycle arrest, ER stress and autophagy". International Journal of Oncology 47.4 (2015): 1257-1265.
Chicago
Choi, J. Y., Hong, W. G., Cho, J. H., Kim, E. M., Kim, J., Jung, C., Hwang, S., Um, H., Park, J. K."Podophyllotoxin acetate triggers anticancer effects against non-small cell lung cancer cells by promoting cell death via cell cycle arrest, ER stress and autophagy". International Journal of Oncology 47, no. 4 (2015): 1257-1265. https://doi.org/10.3892/ijo.2015.3123