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Cancer Chemotherapy and Pharmacology

, Volume 77, Issue 1, pp 63–75 | Cite as

Malformin A1 promotes cell death through induction of apoptosis, necrosis and autophagy in prostate cancer cells

  • Yongqing Liu
  • Ming Wang
  • Dawei Wang
  • Xiaobin Li
  • Wei Wang
  • Hongxiang Lou
  • Huiqing YuanEmail author
Original Article

Abstract

Purpose

Malformin A1 (MA1), a cyclopentapeptide isolated from fungal origin, has been identified to induce varieties of intriguing biological activities. Here, we reported the mode of mechanism underlying MA1-mediated cytotoxicity through induction of apoptosis, necrosis and autophagy in prostate cancer (PCa) cells.

Methods

Human PCa cells PC3 and LNCaP were treated with MA1, and cell viability, apoptosis, necrosis, mitochondrial damage, oxidative stress and autophagy were analyzed, respectively. Pharmacological inhibitors, transient transfection of plasmids and siRNAs were then used to identify the roles of oxidative stress and autophagy in MA1-triggered cell death.

Results

In both PC3 and LNCaP cells, MA1 inhibited cell proliferation and triggered oxidative stress via the rapid accumulation of reactive oxygen species and a decrease in mitochondrial transmembrane potential. Mitochondrial damage by MA1 triggered caspase activation and intracellular ATP deletion, leading to apoptosis and necrosis, respectively. Meanwhile, MA1 activated autophagy as indicated by conversion of LC3BI to LC3BII and increased GFP-tagged LC3B punctate dots. Pharmacological inhibition of autophagy or knocking down LC3B attenuated MA1-mediated cell death. Excessive oxidative stress and decreased ATP stimulated AMPK/mTOR pathway, which led to induction of MA1-mediated autophagy.

Conclusions

Coaction of apoptotic, necrotic and autophagic cell death induced by mitochondrial damage defines a novel mechanism contributing to the growth suppression of MA1 in prostate cancer cells, and activation of autophagy might be a potential strategy for improving its chemotherapeutic effects.

Keywords

Malformin A1 Oxidative stress Mitochondrial damage Apoptosis Necrosis Autophagy 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81273533, 81172956), and Program for Changjiang Scholars and Innovative Research Team in University (IRT13028).

Compliance with ethical standards

Conflict of interst

None.

Supplementary material

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Yongqing Liu
    • 1
    • 2
  • Ming Wang
    • 3
  • Dawei Wang
    • 1
  • Xiaobin Li
    • 2
  • Wei Wang
    • 1
  • Hongxiang Lou
    • 2
  • Huiqing Yuan
    • 1
    Email author
  1. 1.Department of Biochemistry and Molecular BiologyShandong University School of MedicineJinanChina
  2. 2.Department of Natural Product ChemistryShandong University School of Pharmaceutical SciencesJinanChina
  3. 3.Department of BiochemistryWannan Medical CollegeWuhuChina

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