Disruption of endolysosomal trafficking pathways in glioma cells by methuosis-inducing indole-based chalcones

Mbah, Nneka E.; Overmeyer, Jean H.; Maltese, William A.

doi:10.1007/s10565-016-9369-2

Cited by 31 publications

(26 citation statements)

References 73 publications

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“…Cells undergoing methuosis initially exhibit massive vacuolization of macropinosomes and late endosomes. Our recent studies indicate that this is due to defective trafficking of late endosomes to lysosomes, with concomitant homotypic fusion of the affected vesicular compartments [5]. The defect in lysosome-directed trafficking also affects autophagic flux, with resultant accumulation of autophagosomes [5].…”

Section: Introductionmentioning

confidence: 99%

“…Our recent studies indicate that this is due to defective trafficking of late endosomes to lysosomes, with concomitant homotypic fusion of the affected vesicular compartments [5]. The defect in lysosome-directed trafficking also affects autophagic flux, with resultant accumulation of autophagosomes [5]. Ultimately, the integrity of the cell membrane is compromised and the vacuolated cells rupture in a manner reminiscent of necrosis.…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, we found that minor structural modifications of the indole ring yielded a functionally distinct sub-group of IPPs that retained the ability to induce robust morphological vacuolization, with greatly reduced cytotoxicity [21, 22]. By comparing the effects of MOMIPP with one of the non-lethal analogs (MO P IPP; with propyl substituted for methyl at the 2-position of the indole ring), we noted that cells treated with MOMIPP had more severe inhibition of endolysosomal degradation pathways for EGF and LDL receptors [5]. Coincidentally, MOMIPP shows stronger binding affinity (lower K d ) for PIKfyve than the non-lethal analogs [10], despite the fact that the cells treated with these compounds have similar vacuolated morphologies.…”

Section: Introductionmentioning

confidence: 99%

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The JNK signaling pathway plays a key role in methuosis (non-apoptotic cell death) induced by MOMIPP in glioblastoma

Mbah

Overmeyer

et al. 2019

BMC Cancer

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BackgroundSynthetic indolyl- pyridinyl- propenones (IPPs) induce methuosis, a form of non-apoptotic cell death, in glioblastoma and other cancer cell lines. Methuosis is characterized by accumulation of cytoplasmic vacuoles derived from macropinosomes and late endosomes, followed by metabolic failure and rupture of the plasma membrane. However, not all IPPs that cause vacuolization are cytotoxic. The main goals of the present study were to identify key signaling pathways that contribute to methuosis induced by cytotoxic IPPs and to evaluate the anti-tumor potential of a prototype IPP in vivo.MethodsWe utilized metabolic flux analysis, glucose uptake, immunoblotting, and selective pharmacological inhibitors to compare the effects of closely related cytotoxic and non-cytotoxic IPPs in cultured glioblastoma cells. To determine whether the use of methuosis-inducing IPPs might be feasible in a therapeutic context, we quantified the distribution of our lead IPP compound, MOMIPP, in mouse plasma and brain, and tested its ability to inhibit tumor growth in an intracerebral glioblastoma xenograft model.ResultsThe cytotoxic IPP compound, MOMIPP, causes early disruptions of glucose uptake and glycolytic metabolism. Coincident with these metabolic changes, MOMIPP selectively activates the JNK1/2 stress kinase pathway, resulting in phosphorylation of c-Jun, Bcl-2 and Bcl-xL. At the same concentration, the non-cytotoxic analog, MOPIPP, does not activate these pathways. Pharmacologic inhibition of JNK activity promotes survival, even when cells are extensively vacuolated, but suppression of c-Jun transcriptional activity offers no protection. MOMIPP readily penetrates the blood-brain barrier and is moderately effective in suppressing progression of intracerebral glioblastoma xenografts.ConclusionsThe results suggest that interference with glucose uptake and induction of JNK-mediated phosphorylation of pro-survival members of the Bcl-2 family represent key events in the methuosis death process. In addition to providing new insights into the underlying molecular mechanism of methuosis, the results indicate that compounds of the cytotoxic IPP class may have potential for further development as therapeutic agents for brain tumors.Electronic supplementary materialThe online version of this article (10.1186/s12885-019-5288-y) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The JNK signaling pathway plays a key role in methuosis (non-apoptotic cell death) induced by MOMIPP in glioblastoma

Mbah

Overmeyer

et al. 2019

BMC Cancer

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“…Methuosis is a nonapoptotic form of cell death characterized by cell sprouting that induces a mutual fusion between different cells and the accumulation of vacuoles in the vesicles [20,21]. We investigated the possible molecular mechanisms through which EPS causes cell death via methuosis and found that previous studies have shown how RAS is related to methuosis [20][21][22].…”

Section: Discussionmentioning

confidence: 98%

Ethanol Extract of the Infructescence of Platycarya strobilacea Sieb. et Zucc. Induces Methuosis of Human Nasopharyngeal Carcinoma Cells

Liu

Ying

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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The infructescence of Platycarya strobilacea Sieb. et Zucc. (PS) has been used in the treatment of rhinitis and sinusitis in clinical practice. Our preliminary study showed that an ethanol extract of the infructescence of PS (EPS) had significant antinasopharyngeal carcinoma (NPC) effects in vitro. However, the mechanism underlying the NPS cell death induced by EPS remains unclear. The aim of the present study was to investigate the inhibitory effects of EPS on NPC cells and to elucidate the underlying mechanism. The effects of EPS on NPC cells were investigated in CNE1 and CNE2 cells in vitro. In EPS-treated cells, the cell morphological changes were evaluated through fluorescence microscope, transmission electron microscopy, and flow cytometry. The underlying mechanism was analyzed via network pharmacology and further verified by western blot analysis. The anticancer effects of EPS were associated with the generation of CNE1 and CNE2 cell fusion and vacuoles, the perturbation of lysosomal vesicle transportation, and the induction of methuosis. The network pharmacology and western blot results indicated that the effect of EPS in NPC cells might be achieved via regulation of the Ras proto-oncogene (RAS)/mitogen-activated protein kinase (MAPK) signaling pathway and the transcription factor c-Fos proto-oncogene (c-FOS) and its downstream genes. EPS induces NPC cell death through methuosis. The mechanism might be related to regulation of the transcription factor c-FOS and its downstream genes.

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“…Autophagy is the machinery of the intracellular degradation process, which is also the part of the intracellular membrane system and is linked to the endolysosomal pathway [51,53]. Furthermore, recent studies have been accumulating concerning a new type of cell death associated with large vacuoles, named methuosis, although it is thought Cytotoxicity that this type of cell death does not require caspases [54,55]. Some of the machineries mentioned above might be related to the cell death caused by TiNSs.…”

Section: Discussionmentioning

confidence: 99%

Toxicity of Titanate Nanosheets on Human Immune Cells

Nishimura¹,

Yoshioka²,

Kumagai-Τakei³

et al. 2018

Cytotoxicity

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Titanium oxide is regarded as a bio-inert material, but studies concerning the toxic effects of titanium dioxide (TiO 2), particularly nano-scaled TiO 2 particles, have been accumulating that indicate nano-scaled TiO 2 particles show more harm and cause greater alteration of immune functions compared with large particles. Inorganic nanosheets have been the focus of increasing interest because of their ultrathin structure, as well as diversity of compounds and structures leading to various functions. Oxide nanosheets are included in the group comprising inorganic nanosheets, and titanate nanosheets (TiNSs) represent a form of oxide nanosheets. We therefore examined the toxicity of nano-scaled 2D materials of TiNSs on human immune cells. Our study revealed that TiNSs have the potential to cause harm through caspase-dependent apoptosis of human peripheral blood mononuclear cells (PBMCs) to the same degree as asbestos. Furthermore, isolated monocytes developed marked vacuoles prior to cell death upon exposure to TiNSs, which were found in the vacuoles and indicated engulfment of TiNSs. A consideration of these findings with the co-localization of vacuoles with endocytosed fluorescence-labeled dextran indicates that TiNSs entered the endosomal pathway, leading to the formation of vacuoles in monocytes and subsequent cell death. TiNSs might therefore affect immune functions through interference of endo-lysosomal functions.

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Disruption of endolysosomal trafficking pathways in glioma cells by methuosis-inducing indole-based chalcones

Cited by 31 publications

References 73 publications

The JNK signaling pathway plays a key role in methuosis (non-apoptotic cell death) induced by MOMIPP in glioblastoma

The JNK signaling pathway plays a key role in methuosis (non-apoptotic cell death) induced by MOMIPP in glioblastoma

Ethanol Extract of the Infructescence of Platycarya strobilacea Sieb. et Zucc. Induces Methuosis of Human Nasopharyngeal Carcinoma Cells

Toxicity of Titanate Nanosheets on Human Immune Cells

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