Autophagonizer, a novel synthetic small molecule, induces autophagic cell death

Choi, In Kwon; Cho, Yoon Sun; Jung, Hye Jin; Kwon, Ho Jeong

doi:10.1016/j.bbrc.2010.02.097

Cited by 16 publications

(18 citation statements)

References 23 publications

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“…The second approach is to design and develop autophagy regulators according to the structural information of Atg proteins (Miller et al, 2010). Recently, additional autophagy regulators have been discovered through such a screening approach (Balgi et al, 2009;Choi et al, 2010;Renna et al, 2010). More studies using these and other approaches are expected to help us in understanding the regulatory network of autophagy and in making the therapeutic modulation of autophagy a reality.…”

Section: Discussionmentioning

confidence: 99%

The regulation of autophagy – unanswered questions

Chen

Klionsky

2011

Journal of Cell Science

544

456

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Commentary 161Introduction Autophagy is a stress-induced catabolic process involving the lysosome (or, in yeast, the analogous vacuole), which is conserved in all eukaryotes (Esclatine et al., 2009; Klionsky, 2005). According to the different pathways by which cargo is delivered to the lysosome or vacuole, autophagy is divided into three main types: chaperone-mediated autophagy (CMA), microautophagy and macroautophagy (Klionsky, 2005). CMA is a process that has been characterized in higher eukaryotes but not in yeast. In CMA, a chaperone protein binds first to its cytosolic target substrate and then to a receptor on the lysosomal membrane where the unfolding of the protein occurs. The unfolded cytosolic target protein is subsequently translocated directly into the lysosome for its degradation (Massey et al., 2004). Microautophagy translocates cytoplasmic materials into the lysosome or vacuole for degradation by either direct invagination, protrusion, or septation of the lysosomal or vacuolar membrane (Wang and Klionsky, 2004). Macroautophagy is characterized by the formation of a cytosolic double-membrane vesicle, the autophagosome. During macroautophagy, cytoplasmic proteins, organelles or other materials are surrounded by phagophores, which expand and close to form autophagosomes. These autophagosomes fuse with lysosomes (or vacuoles) to form autolysosomes, in which the cytoplasmic cargos are degraded by resident hydrolases. The resulting degradation products are then transported back into the cytosol through the activity of membrane permeases for reuse (Fig. 1). In the yeast Saccharomyces cerevisiae, microautophagy engulfs cytosolic materials through an autophagic tube, which then scissions within the vacuole to release the contents into a vesicle within the vacuolar lumen for degradation (Uttenweiler and Mayer, 2008); microautophagy-like processes, such as one type of selective peroxisome degradation, are slightly different and involve targeted sequestration of the cargo (Dunn et al., 2005). The process and mechanism of microautophagy in mammalian cells are still not clear (Cuervo, 2004). Among the three main forms of autophagy, macroautophagy is the most widely studied and best characterized process. In this review, we will thus focus on macroautophagy, hereafter referred to as autophagy.Although autophagy is generally considered to be nonspecific, there are many examples of selective autophagy, including mitophagy (for mitochondria), ribophagy (for ribosomes), pexophagy (for peroxisomes) and reticulophagy (for the endoplasmic reticulum, ER) (He and Klionsky, 2009). By contrast, the yeast cytoplasm-to-vacuole targeting (Cvt) pathway is a biosynthetic pathway used to transport the vacuolar hydrolases -mannosidase and aminopeptidase I (Ape1) from the cytosol to the vacuole under normal growth conditions. As the Cvt pathway shares the core autophagy machinery, which is composed of 17 autophagy-related (Atg) proteins found in all autophagy pathways, it is also defined as a type of selective autophagy (Inoue...

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Section: Discussionmentioning

confidence: 99%

The regulation of autophagy – unanswered questions

Chen

Klionsky

2011

Journal of Cell Science

544

456

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“…Furthermore, more experiments conducted in other types of cancer cells may provide more data to identify signaling pathways involved in dioscin-induced autophagy. Autophagic agonists have been described as anticancer drugs [32, 40, 41] with various compounds being shown to induce death in tumor cells with defective apoptotic machinery [42, 43]. Thus, with the capability to induce both the apoptotic and autophagic pathways, dioscin may be a good candidate for antitumor treatment.…”

Section: Discussionmentioning

confidence: 99%

Autophagy Inhibition Enhances Apoptosis Induced by Dioscin in Huh7 Cells

Hsieh

Yang

Hsieh

et al. 2012

Evidence-Based Complementary and Alternative Medicine

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Extensive research results support the application of herbal medicine or natural food as an augment during therapy for various cancers. However, the effect of dioscin on tumor cells autophagy has not been clearly clarified. In this study, the unique effects of dioscin on autophagy of hepatoma cells were investigated. Results found that dioscin induced caspase-3- and -9-dependent cell apoptosis in a dose-dependent manner. Moreover, inhibition of ERK1/2 phosphorylation significantly abolished the dioscin-induced apoptosis. In addition, dioscin triggered cell autophagy in early stages. With autophagy inhibitors to hinder the autophagy process, dioscin-induced cell apoptosis was significantly enhanced. An inhibition of caspase activation did not affect the dioscin-induced LC3-II protein expression. Based on the results, we believed that while apoptosis was blocked, dioscin-induced autophagy process also diminished in Huh7 cells. In conclusion, this study indicates that dioscin causes autophagy in Huh7 cells and suggests that dioscin has a cytoprotective effect.

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“…AO is a weak base that accumulates in AVOs. The AVOs can be quantified based on the fact that the increase in the intensity of the red fluorescence is proportional to the degree of acidity (17). For the FACS analysis, A549 cells (5x10 6 ) were placed in a 100-mm culture dish and treated with 0, 50 or 100 µg/ml of MRGX.…”

Section: Methodsmentioning

confidence: 99%

Modified Panax ginseng extract regulates autophagy by AMPK signaling in A549 human lung cancer cells

Yoo

Kim²,

et al. 2017

Oncology Reports

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Abstract. Panax ginseng has been used worldwide as a traditional medicine for the treatment of cancer and other diseases. The antiproliferative activity of ginseng has been increased after enzymatic processing of ginseng saponin, which may result in the accumulation of minor saponins, such as Rh2, Rg3, compound K and protopanaxatriol type (PPT) in modified regular ginseng extract (MRGX). In the present study, the anticancer activity and the associated mechanisms of MRGX were investigated using A549 human lung cancer cells. To elucidate the mechanisms underlying the effects of MRGX, we performed a microarray analysis of gene expression in the A549 cells. Molecular mechanisms that were associated with the anticancer activity of MRGX were studied, with a special focus on the autophagy-related multiple signaling pathways in lung cancer cells. Microarray analyses elucidated autophagyrelated genes affected by MRGX. Administration of MRGX at 100 µg/ml induced punctate cytoplasmic expression of LC3, Beclin-1 and ATG5 and increased expression of endogenous LC3-II whereas 50 µg/ml did not inhibit the proliferation of A549 cells. Compared to the control cells, in cells treated with MRGX at 100 µg/ml, the level of p-Akt was increased, while that of mTOR-4EBP1 was decreased. Downregulation of mTOR and 4EBP1 in the MRGX-treated cells was found not to be a p-Ulk (S757)-dependent pathway, but a p-Ulk (S317)-dependent autophagic pathway, using AMPK. These data suggest that MRGX regulates AMPK and induces autophagy in lung cancer cells.

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Autophagonizer, a novel synthetic small molecule, induces autophagic cell death

Cited by 16 publications

References 23 publications

The regulation of autophagy – unanswered questions

The regulation of autophagy – unanswered questions

Autophagy Inhibition Enhances Apoptosis Induced by Dioscin in Huh7 Cells

Modified Panax ginseng extract regulates autophagy by AMPK signaling in A549 human lung cancer cells

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