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The short chain cell-permeable ceramide (C6) restores cell apoptosis and perifosine sensitivity in cultured glioblastoma cells

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Abstract

Primary glioblastoma multiforme is the most malignant form of astrocytic tumor with an average survival of approximately 12–14 months. The combination of novel Akt inhibitors with anti-cancer therapeutics has achieved improved anti-tumor efficiency. In the current study, we examined the synergistic anti-cancer ability of Akt inhibitor perifosine in combination with short-chain ceramide (C6) against glioblastoma cells (U87MG and U251MG), and studied the underlying mechanisms. We found that perifosine, which blocked Akt/mammalian target of rapamycin activation, only induced moderate cell death and few cell apoptosis in cultured glioblastoma cells. On the other hand, perifosine administration induced significant protective autophagy, which inhibited cell apoptosis induction. Inhibition of autophagy by 3-methyaldenine or by autophagy-related gene-5 RNA interference significantly enhanced perifosine-induced apoptosis and cytotoxicity. We found that the short chain cell-permeable ceramide (C6) significantly enhanced cytotoxic effects of perifosine in cultured glioblastoma cells. For mechanism study, we observed that ceramide (C6) inhibited autophagy induction to restore cell apoptosis and perifosine sensitivity. In conclusion, our study suggests that autophagy inhibition by ceramide (C6) restores perifosine-induced apoptosis and cytotoxicity in glioblastoma cells.

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Abbreviations

MTT:

3-[4,5-Dimethylthylthiazol-2-yl]-2,5-diphenyltetrazolium bromide

3-MA:

3-Methyaldenine

ATG-5:

Autophagy-related gene-5

Cq:

Chloroquine

FACS:

Fluorescence-activated cell sorting

GBM:

Glioblastoma multiforme

LC3B:

Light chain 3B

mTOR:

Mammalian target of rapamycin

PI3K:

Phosphatidylinositol 3-kinase

ROS:

Reactive oxygen species

RNAi:

RNA interference

TMZ:

Temozolomide

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Acknowledgments

This work is funded by national neutral and science foundation of China.

Conflict of interest

The authors declare no conflict of interests.

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Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Soochow University, No. 188, Shi-zi Street, Suzhou, 215000, Jiangsu, People’s Republic of China

    Li-sen Qin, Zheng-quan Yu & Shi-ming Zhang

  2. Department of Neurosurgery, Yan-cheng Pavilion Lake District People’s Hospital, 194 Jian-jun Road, Pavilion Lake District, Yan-Cheng, 224001, People’s Republic of China

    Li-sen Qin, Guan Sun, Jian Zhu, Jin Xu, Jun Guo & Lin-shan Fu

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  1. Li-sen Qin
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  2. Zheng-quan Yu
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  3. Shi-ming Zhang
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  4. Guan Sun
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  5. Jian Zhu
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  6. Jin Xu
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  7. Jun Guo
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  8. Lin-shan Fu
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Correspondence to Shi-ming Zhang or Lin-shan Fu.

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Qin, Ls., Yu, Zq., Zhang, Sm. et al. The short chain cell-permeable ceramide (C6) restores cell apoptosis and perifosine sensitivity in cultured glioblastoma cells. Mol Biol Rep 40, 5645–5655 (2013). https://doi.org/10.1007/s11033-013-2666-4

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  • DOI: https://doi.org/10.1007/s11033-013-2666-4

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