Dual targeting of energy metabolism and lysosomes as an anticancer strategy; It is not all about autophagy
2021
Preuzimanje 🢃
Autori:
Harhaji-Trajković, LjubicaKosić, Milica
Paunović, Verica
Ristić, Biljana
Bošnjak, Mihajlo
Zogović, Nevena
Mandić, Miloš
Tovilović-Kovačević, Gordana
Janjetović, Kristina
Trajković, Vladimir
Ostala autorstva
Đorđić Crnogorac, MarijaNedeljković, Milica
Tip dokumenta:
Konferencijski prilog (Objavljena verzija)
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© 2021 Srpsko društvo istraživača raka
Metapodaci
Prikaz svih podataka o dokumentuApstrakt:
Background: Intensive proliferation of tumor cells consumes a lot of energy. In nutrient deficiency
substrates for energy metabolism are obtained by lysosomal degradation of unnecessary/dysfunctional
intracellular organelles/molecules in the process of autophagy. Leakage of enlarged unstable lysosomes,
which characterize tumor cells, causes cell death. We investigated antitumor effect of combined targeting
of lysosomes/autophagy and energy metabolism. Material and Methods: Toxicity against U251 human
glioma and B16 mouse melanoma cells was measured by viability tests. Type/mechanisms of cell death
were determined by flow cytometry, immunoblot, fluorescent/electron microscopy and confirmed by
appropriate genetic/pharmacological inhibitors. Therapeutic potential was estimated in B16 melanoma bearing C57Bl/6 mice. Results: In the first study, lysosomotropic autophagy inhibitor chloroquine (CQ)
rapidly killed tumor cells incubated in the absence of serum. CQ-induced lysosomal destabilization
triggered: oxidative stress, mitochondrial depolarization, and mixed apoptosis/necrosis of serum-deprived
cells. In the second study, lysosomal detergent N-dodecylimidazole (NDI) synergized in antitumor activity
with the glycolytic inhibitor 2-deoxy-D-glucose (2DG). NDI-triggered release of lysosomal enzymes into the
cytoplasm caused mitochondrial damage and blocked oxidative phosphorylation, which synergized with
2DG-mediated glycolysis block in ATP reduction, oxidative stress, and necrosis. Interestingly, although both
serum deprivation and 2DG stimulated autophagy, CQ- and NDI-induced autophagy suppression was
irrelevant for their cytotoxicity. Importantly, CQ+food restriction and 2DG+NDI reduced melanoma growth
in vivo. Conclusion: Autophagy independent antitumor effects of combined energy metabolism suppression
and lysosomal destabilization might be exploited in cancer therapy.
Ključne reči:
Autophagy; Combined Therapy; Energy Metabolism; LysosomesU:
- Đorđević Crnogorac M, Nedeljković M, editors. Abstract book: 5th Congress of the Serbian Association for Cancer Research with International Participation SDIR-5: Translational Potential of Cancer Research in Serbia; 2021 Dec 3; Virtual event. Beograd: Srpsko društvo istraživača raka; 2021. p. 8.