Betulinic acid-induced mitochondria-dependent cell death is counterbalanced by an autophagic salvage response.
Betulinic acid (BetA) is a plant-derived pentacyclic triterpenoid that exerts potent anti-cancer effects in vitro and in vivo. It was shown to induce apoptosis via a direct effect on mitochondria. This is largely independent of proapoptotic BAK and BAX, but can be inhibited by cyclosporin A (CsA), an inhibitor of the permeability transition (PT) pore. Here we show that blocking apoptosis with general caspase inhibitors did not prevent cell death, indicating that alternative, caspase-independent cell death pathways were activated. BetA did not induce necroptosis, but we observed a strong induction of autophagy in several cancer cell lines. Autophagy was functional as shown by enhanced flux and degradation of long-lived proteins. BetA-induced autophagy could be blocked, just like apoptosis, with CsA, suggesting that autophagy is activated as a response to the mitochondrial damage inflicted by BetA. As both a survival and cell death role have been attributed to autophagy, autophagy-deficient tumor cells and mouse embryo fibroblasts were analyzed to determine the role of autophagy in BetA-induced cell death. This clearly established BetA-induced autophagy as a survival mechanism and indicates that BetA utilizes an as yet-undefined mechanism to kill cancer cells.
Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands.
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L
Potze
Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands.
F B
FB
Mullauer
Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands.
S
S
Colak
Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands.
J H
JH
Kessler
Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands.
J P
JP
Medema
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009336:Necrosis; D053978:Pentacyclic Triterpenes; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*; D000094062:Betulinic Acid
D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D016572:Cyclosporine; D000094062:Betulinic Acid