BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Mitochondrial dysfunction induced by callyspongiolide promotes autophagy-dependent cell death

  • Received : 2021.03.05
  • Accepted : 2021.04.01
  • Published : 2021.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

Callyspongiolide is a marine macrolide known to induce caspase-independent cancer cell death. While its toxic effects have been known, the mechanism leading to cell death is yet to be identified. We report that Callyspongiolide R form at C-21 (cally2R) causes mitochondrial dysfunction by inhibiting mitochondrial complex I or II, leading to a disruption of mitochondrial membrane potential and a deprivation of cellular energy. Subsequently, we observed, using electron microscopy, a drastic formation of autophagosome and mitophagy. Supporting these data, LC3, an autophagosome marker, was shown to co-localize with LAMP2, a lysosomal protein, showing autolysosome formation. RNA sequencing results indicated the induction of hypoxia and blocking of EGF-dependent pathways, which could be caused by induction of autophagy. Furthermore, mTOR and AKT pathways preventing autophagy were repressed while AMPK was upregulated, supporting autophagosome progress. Finally, the combination of cally2R with known anti-cancer drugs, such as gefitinib, sorafenib, and rapamycin, led to synergistic cell death, implicating potential therapeutic applications of callyspongiolide for future treatments.

Keywords

Acknowledgement

The authors are grateful for the use of Seoul National University's imaging facility and we thank the technicians for technical support. We are grateful to Drs. Sammy C.S. Lee and Myeong Jin Yoon for their help with critical reading and improving the manuscript.

References

  1. Linder B, Kogel D (2019) Autophagy in cancer cell death. Biology (Basel) 8, 82 https://doi.org/10.3390/biology8040082
  2. Akkoc Y, Gozuacik D (2018) Autophagy and liver cancer. Turk J Gastroenterol 29, 270-282 https://doi.org/10.5152/tjg.2018.150318
  3. Kim SY, Hwangbo H, Kim MY et al (2021) Coptisine induces autophagic cell death through down-regulation of PI3K/Akt/mTOR signaling pathway and up-regulation of ROS-mediated mitochondrial dysfunction in hepatocellular carcinoma Hep3B cells. Arch Biochem Biophys 697, 108688 https://doi.org/10.1016/j.abb.2020.108688
  4. Sanchez-Alvarez M, Strippoli R, Donadelli M, Bazhin AV, Cordani M (2019) Sestrins as a therapeutic bridge between ROS and autophagy in cancer. Cancers (Basel) 11, 1415 https://doi.org/10.3390/cancers11101415
  5. Bao J, Liu B, Wu C (2020) The prospects of therapeutic potential and drug development targeting autophagy in cancer. Adv Exp Med Biol 1207, 663-679 https://doi.org/10.1007/978-981-15-4272-5_49
  6. Nyfeler B, Eng CH (2016) Revisiting autophagy addiction of tumor cells. Autophagy 12, 1206-1207 https://doi.org/10.1080/15548627.2016.1170265
  7. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029-1033 https://doi.org/10.1126/science.1160809
  8. Bernardi P (1999) Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol Rev 79, 1127-1155 https://doi.org/10.1152/physrev.1999.79.4.1127
  9. Faubert B, Vincent EE, Poffenberger MC, Jones RG (2015) The AMP-activated protein kinase (AMPK) and cancer: many faces of a metabolic regulator. Cancer Lett 356, 165-170 https://doi.org/10.1016/j.canlet.2014.01.018
  10. Vyas S, Zaganjor E, Haigis MC (2016) Mitochondria and cancer. Cell 166, 555-566 https://doi.org/10.1016/j.cell.2016.07.002
  11. Toyama EQ, Herzig S, Courchet J et al (2016) Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351, 275-281 https://doi.org/10.1126/science.aab4138
  12. Pham CD, Hartmann R, Bohler P et al (2014) Callyspongiolide, a cytotoxic macrolide from the marine sponge Callyspongia sp. Org Lett 16, 266-269 https://doi.org/10.1021/ol403241v
  13. Pommier Y, Sordet O, Antony S, Hayward RL, Kohn KW (2004) Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks. Oncogene 23, 2934-2949 https://doi.org/10.1038/sj.onc.1207515
  14. Chang YH, Yang YL, Chen CM, Chen HY (2015) Apoptosis pathway signature for prediction of treatment response and clinical outcome in childhood high risk B-Precursor acute lymphoblastic leukemia. Am J Cancer Res 5, 1844-1853
  15. Manoni F, Rumo C, Li L, Harran PG (2018) Unconventional fragment usage enables a concise total synthesis of (-)-callyspongiolide. J Am Chem Soc 140, 1280-1284 https://doi.org/10.1021/jacs.7b13591
  16. Wang Y, Xu W, Yan Z et al (2018) Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways. J Exp Clin Cancer Res 37, 63 https://doi.org/10.1186/s13046-018-0731-5
  17. Bjorkoy G, Lamark T, Pankiv S, Overvatn A, Brech A, Johansen T (2009) Monitoring autophagic degradation of p62/SQSTM1. Methods Enzymol 452, 181-197 https://doi.org/10.1016/S0076-6879(08)03612-4
  18. Fernandez-Marcos PJ, Serrano M (2016) Mitochondrial damage induces senescence with a twisted arm. Cell Metab 23, 229-230 https://doi.org/10.1016/j.cmet.2016.01.012
  19. Ahmad M, Wolberg A, Kahwaji CI (2021) Biochemistry, electron transport chain. StatPearls Publishing; 2021 Jan. 2020 Sep 8
  20. Agani FH, Pichiule P, Chavez JC, LaManna JC (2000) The role of mitochondria in the regulation of hypoxia-inducible factor 1 expression during hypoxia. J Biol Chem 275, 35863-35867 https://doi.org/10.1074/jbc.M005643200
  21. Huang Y, Zhou S, He C et al (2018) Phenformin alone or combined with gefitinib inhibits bladder cancer via AMPK and EGFR pathways. Cancer Commun (Lond) 38, 50 https://doi.org/10.1186/s40880-018-0319-7
  22. Fogarty S, Ouyang Y, Li L et al (2020) Callyspongiolide Is a potent inhibitor of the vacuolar ATPase. J Nat Prod 83, 3381-3386 https://doi.org/10.1021/acs.jnatprod.0c00813
  23. Fethiere J, Venzke D, Diepholz M et al (2004) Building the stator of the yeast vacuolar-ATPase: specific interaction between subunits E and G. J Biol Chem 279, 40670-40676 https://doi.org/10.1074/jbc.M407086200