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

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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.

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References

  1. Strobel G, Daisy B, Castillo U, Harper J (2004) Natural products from endophytic microorganisms. J Nat Prod 67(2):257–268

    Article  PubMed  CAS  Google Scholar 

  2. Gunatilaka AA (2006) Natural products from plant-associated microorganisms: distribution, structural diversity, bioactivity, and implications of their occurrence. J Nat Prod 69(3):509–526

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Li XB, Xie F, Liu SS, Li Y, Zhou JC, Liu YQ, Yuan HQ, Lou HX (2013) Naphtho-gamma-pyrones from Endophyte Aspergillus niger occurring in the liverwort Heteroscyphus tener (Steph.) Schiffn. Chem Biodivers 10(7):1193–1201

    Article  PubMed  CAS  Google Scholar 

  4. Zhan J, Gunaherath GM, Wijeratne EM, Gunatilaka AA (2007) Asperpyrone D and other metabolites of the plant-associated fungal strain Aspergillus tubingensis. Phytochemistry 68(3):368–372

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Chomcheon P, Wiyakrutta S, Sriubolmas N, Ngamrojanavanich N, Isarangkul D, Kittakoop P (2005) 3-Nitropropionic acid (3-NPA), a potent antimycobacterial agent from endophytic fungi: is 3-NPA in some plants produced by endophytes? J Nat Prod 68(7):1103–1105

    Article  PubMed  CAS  Google Scholar 

  6. Bodanszky M, Stahl GL (1974) The structure and synthesis of malformin A. Proc Natl Acad Sci USA 71(7):2791–2794

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Yoshizawa T, Tsuchiya Y, Morooka N, Sawada Y (1975) Malformin Al as a mammalian toxicant from aspergillus niger. Agric Biol Chem 39(6):1325–1326

    Article  CAS  Google Scholar 

  8. Takahashi N, Curtis RW (1961) Isolation and characterization of malformin. Plant Physiol 36(1):30–36

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Curtis RW (1961) Studies on response of bean seedlings and corn roots to malformin. Plant Physiol 36(1):37–43

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Koizumi Y, Hasumi K (2002) Enhancement of fibrinolytic activity of U937 cells by malformin A1. J Antibiot 55(1):78–82

    Article  PubMed  CAS  Google Scholar 

  11. Koizumi Y, Fukudome H, Hasumi K (2011) Fibrinolytic activation promoted by the cyclopentapeptide malformin: involvement of cytoskeletal reorganization. Biol Pharm Bull 34(9):1426–1431

    Article  PubMed  CAS  Google Scholar 

  12. Suda S, Curtis RW (1966) Antibiotic properties of malformin. Appl Microbiol 14(3):475–476

    PubMed  CAS  PubMed Central  Google Scholar 

  13. Kojima Y, Sunazuka T, Nagai K, Hirose T, Namatame M, Ishiyama A, Otoguro K, Omura S (2009) Solid-phase synthesis and biological activity of malformin C and its derivatives. J Antibiot 62(12):681–686

    Article  PubMed  CAS  Google Scholar 

  14. Nadella P, Shapiro C, Otterson GA, Hauger M, Erdal S, Kraut E, Clinton S, Shah M, Stanek M, Monk P, Villalona-Calero MA (2002) Pharmacobiologically based scheduling of capecitabine and docetaxel results in antitumor activity in resistant human malignancies. J Clin Oncol 20(11):2616–2623

    Article  PubMed  CAS  Google Scholar 

  15. Hagimori K, Fukuda T, Hasegawa Y, Omura S, Tomoda H (2007) Fungal malformins inhibit bleomycin-induced G2 checkpoint in Jurkat cells. Biol Pharm Bull 30(8):1379–1383

    Article  PubMed  CAS  Google Scholar 

  16. Liu YQ, Hu XY, Lu T, Cheng YN, Young CY, Yuan HQ, Lou HX (2012) Retigeric acid B exhibits antitumor activity through suppression of nuclear factor-kappaB signaling in prostate cancer cells in vitro and in vivo. PLoS One 7(5):e38000

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Liu YQ, Ji Y, Li XZ, Tian KL, Yf Young C, Lou HX, Yuan HQ (2013) Retigeric acid B-induced mitophagy by oxidative stress attenuates cell death against prostate cancer cells in vitro. Acta Pharmacol Sin 34(9):1183–1191

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Liu Y, Gao F, Jiang H, Niu L, Bi Y, Young CY, Yuan H, Lou H (2013) Induction of DNA damage and ATF3 by retigeric acid B, a novel topoisomerase II inhibitor, promotes apoptosis in prostate cancer cells. Cancer Lett 337(1):66–76

    Article  PubMed  CAS  Google Scholar 

  19. Wang Y, Wang L, Hu Z, Ji Y, Lin Z, Yuan H, Ji M, Lou H (2013) A novel derivative of riccardin D induces cell death through lysosomal rupture in vitro and inhibits tumor growth in vivo. Cancer Lett 329(2):207–216

    Article  PubMed  CAS  Google Scholar 

  20. Li W, Sun W, Yu X, Du L, Li M (2012) Coumarin-based fluorescent probes for H2S detection. J Fluoresc 23(1):181–186

    Article  PubMed  Google Scholar 

  21. Lin Z, Guo Y, Gao Y, Wang S, Wang X, Xie Z, Niu H, Chang W, Liu L, Yuan H, Lou H (2015) ent-Kaurane diterpenoids from Chinese liverworts and their antitumor activities through Michael Addition as detected in situ by a Fluorescence Probe. J Med Chem 58(9):3944–3956

    Article  PubMed  CAS  Google Scholar 

  22. Villena J, Henriquez M, Torres V, Moraga F, Diaz-Elizondo J, Arredondo C, Chiong M, Olea-Azar C, Stutzin A, Lavandero S, Quest AF (2008) Ceramide-induced formation of ROS and ATP depletion trigger necrosis in lymphoid cells. Free Radic Biol Med 44(6):1146–1160

    Article  PubMed  CAS  Google Scholar 

  23. Zoratti M, Szabo I (1995) The mitochondrial permeability transition. Biochim Biophys Acta 1241(2):139–176

    Article  PubMed  Google Scholar 

  24. Fukai T, Ushio-Fukai M (2011) Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 15(6):1583–1606

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Raza H (2011) Dual localization of glutathione S-transferase in the cytosol and mitochondria: implications in oxidative stress, toxicity and disease. FEBS J 278(22):4243–4251

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Taira T, Saito Y, Niki T, Iguchi-Ariga SM, Takahashi K, Ariga H (2004) DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep 5(2):213–218

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. He S, Yaung J, Kim YH, Barron E, Ryan SJ, Hinton DR (2008) Endoplasmic reticulum stress induced by oxidative stress in retinal pigment epithelial cells. Graefes Arch Clin Exp Ophthalmol 246(5):677–683

    Article  PubMed  CAS  Google Scholar 

  28. Krum SA, la Rosa Dalugdugan Ed, Miranda-Carboni GA, Lane TF (2010) BRCA1 forms a functional complex with gamma-H2AX as a late response to genotoxic stress. J Nucleic Acids 2010:801594

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kroemer G, Marino G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40(2):280–293

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. VanderWeele DJ, Zhou R, Rudin CM (2004) Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin. Mol Cancer Ther 31(2):1605–1613

    Google Scholar 

  31. Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12(9):814–822

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Li L, Chen Y, Gibson SB (2013) Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activation. Cell Signal 25(1):50–65

    Article  PubMed  CAS  Google Scholar 

  33. Dando I, Donadelli M, Costanzo C, Dalla Pozza E, D’Alessandro A, Zolla L, Palmieri M (2013) Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells. Cell Death Dis 4:e664

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Burdon RH (1995) Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Radic Biol Med 18(4):775–794

    Article  PubMed  CAS  Google Scholar 

  35. Ferrin G, Linares CI, Muntane J (2011) Mitochondrial drug targets in cell death and cancer. Curr Pharm Des 17(20):2002–2016

    Article  PubMed  CAS  Google Scholar 

  36. Dickinson DA, Forman HJ (2002) Cellular glutathione and thiols metabolism. Biochem Pharmacol 64(5–6):1019–1026

    Article  PubMed  CAS  Google Scholar 

  37. Chatterjee A (2013) Reduced glutathione: a radioprotector or a modulator of DNA-repair activity? Nutrients 5(2):525–542

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Turrens JF, Boveris A (1980) Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochem J 191(2):421–427

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Han Y, Chen JZ (2013) Oxidative stress induces mitochondrial DNA damage and cytotoxicity through independent mechanisms in human cancer cells. Biomed Res Int 2013:825065

    PubMed  PubMed Central  Google Scholar 

  40. Kono H, Rock KL (2008) How dying cells alert the immune system to danger. Nat Rev Immunol 8(4):279–289

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Lieberthal W, Menza SA, Levine JS (1998) Graded ATP depletion can cause necrosis or apoptosis of cultured mouse proximal tubular cells. Am J Physiol 274(2 Pt 2):F315–F327

    PubMed  CAS  Google Scholar 

  42. Jaeschke H, McGill MR, Ramachandran A (2012) Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Drug Metab Rev 44(1):88–106

    Article  PubMed  CAS  Google Scholar 

  43. Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451(7182):1069–1075

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Russo GL, Russo M, Ungaro P (2013) AMP-activated protein kinase: a target for old drugs against diabetes and cancer. Biochem Pharmacol 86(3):339–350

    Article  PubMed  CAS  Google Scholar 

Download references

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).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, 250012, China

    Yongqing Liu, Dawei Wang, Wei Wang & Huiqing Yuan

  2. Department of Natural Product Chemistry, Shandong University School of Pharmaceutical Sciences, Jinan, 250012, China

    Yongqing Liu, Xiaobin Li & Hongxiang Lou

  3. Department of Biochemistry, Wannan Medical College, Wuhu, 241002, China

    Ming Wang

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  1. Yongqing Liu
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Correspondence to Huiqing Yuan.

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Liu, Y., Wang, M., Wang, D. et al. Malformin A1 promotes cell death through induction of apoptosis, necrosis and autophagy in prostate cancer cells. Cancer Chemother Pharmacol 77, 63–75 (2016). https://doi.org/10.1007/s00280-015-2915-4

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  • DOI: https://doi.org/10.1007/s00280-015-2915-4

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