Abstract
Resistance of cancer cells to chemotherapy remains a significant problem in oncology. Mechanisms regulating programmed cell death, including apoptosis, autophagy or necrosis, in the treatment of cancers have been extensively investigated over the last few decades. Autophagy is now emerging as an important pathway in regulating cell death or survival in cancer therapy. Recent studies demonstrated variety of natural small-molecules could induce autophagic cell death in apoptosis-resistant cancer cells, therefore, discovery of novel autophagic enhancers from natural products could be a promising strategy for treatment of chemotherapy-resistant cancer. By computational virtual docking analysis, biochemical assays, and advanced live-cell imaging techniques, we have identified N-desmethyldauricine (LP-4), isolated from rhizoma of Menispermum dauricum DC as a novel inducer of autophagy. LP-4 was shown to induce autophagy via the Ulk-1-PERK and Ca2+/Calmodulin-dependent protein kinase kinase β (CaMKKβ)-AMPK-mTOR signaling cascades, via mobilizing calcium release through inhibition of SERCA, and importantly, lead to autophagic cell death in a panel of cancer cells, apoptosis-defective and apoptosis-resistant cells. Taken together, this study provides detailed insights into the cytotoxic mechanism of a novel autophagic compound that targeting the apoptosis resistant cancer cells, and new implication on drug discovery from natural products for drug resistant cancer therapy.
Highlights
Autophagy is a cellular degradation mechanism characterized by the formation of double membrane cytoplasmic vesicles, which engulf and degrade cytoplasmic organelles such as mitochondria or endoplasmic reticulum (ER) through lysosomes, thereby, regulate normal cellular integrity and homeostasis of cells
By computational virtual docking analysis and biochemical assays, we demonstrate that LP-4 inhibits sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) in a dose dependent manner which is co-incident with the concentrations leading to autophagic cell death in a panel of cancer cells, apoptosis-defective, and apoptosis-resistant cells
The induction of autophagy may lead to autophagic cell death in some apoptosis-resistant cancers through the inhibition of anti-autophagic proteins (Dalby et al, 2010), identification of novel autophagy inducers from natural products may act as an effective strategy for the discovery of anti-cancer compounds (Turcotte and Giaccia, 2010)
Summary
Autophagy is a cellular degradation mechanism characterized by the formation of double membrane cytoplasmic vesicles, which engulf and degrade cytoplasmic organelles such as mitochondria or ER through lysosomes, thereby, regulate normal cellular integrity and homeostasis of cells. Autophagy can act as either a tumor suppressor by the removal of damaged proteins and organelles, or as a pro-survival mechanism to promote the pathogenesis of tumors (Yang et al, 2011). Clinically approved agents such as rapamycin, plays a therapeutic role in cancer therapy (Opipari et al, 2004; HoyerHansen et al, 2005; Kondo et al, 2005; Chang et al, 2007; Law et al, 2010, 2014; Yang et al, 2011; Wong et al, 2013), mTOR inhibition has adverse effects in protein synthesis, cell proliferation, and immune function (Levine and Kroemer, 2008; Pallet and Legendre, 2013). Drugs that can enhance autophagic cell death, especially in apoptosis-resistant cells, with minimal side effects would be highly desirable
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