Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis

Jennifer S. Carew, Claudia M. Espitia, Juan A. Esquivel, Devalingam Mahalingam, Kevin R. Kelly, Guru Reddy, Francis J. Giles, Steffan T. Nawrocki

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Cellular stress induced by nutrient deprivation, hypoxia, and exposure to many chemotherapeutic agents activates an evolutionarily conserved cell survival pathway termed autophagy. This pathway enables cancer cells to undergo self-digestion to generate ATP and other essential biosynthetic molecules to temporarily avoid cell death. Therefore, disruption of autophagy may sensitize cancer cells to cell death and augment chemotherapy-induced apoptosis. Chloroquine and its analog hydroxychloroquine are the only clinically relevant autophagy inhibitors. Because both of these agents induce ocular toxicity, novel inhibitors of autophagy with a better therapeutic index are needed. Here we demonstrate that the small molecule lucanthone inhibits autophagy, induces lysosomal membrane permeabilization, and possesses significantly more potent activity in breast cancer models compared with chloroquine. Exposure to lucanthone resulted in processing and recruitment of microtubule-associated protein 1 light chain 3 (LC3) to autophagosomes, but impaired autophagic degradation as revealed by transmission electron microscopy and the accumulation of p62/SQSTM1. Microarray analysis, qRT-PCR, and immunoblotting determined that lucanthone stimulated a large induction in cathepsin D, which correlated with cell death. Accordingly, knockdown of cathepsin D reduced lucanthonemediated apoptosis. Subsequent studies using p53+/+ and p53-/- HCT116 cells established that lucanthone induced cathepsin D expression and reduced cancer cell viability independently of p53 status. In addition, lucanthone enhanced the anticancer activity of the histone deacetylase inhibitor vorinostat. Collectively, our results demonstrate that lucanthone is a novel autophagic inhibitor that induces apoptosis via cathepsin D accumulation and enhances vorinostat-mediated cell death in breast cancer models.

Original languageEnglish (US)
Pages (from-to)6602-6613
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number8
DOIs
StatePublished - Feb 25 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Carew, J. S., Espitia, C. M., Esquivel, J. A., Mahalingam, D., Kelly, K. R., Reddy, G., Giles, F. J., & Nawrocki, S. T. (2011). Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. Journal of Biological Chemistry, 286(8), 6602-6613. https://doi.org/10.1074/jbc.M110.151324