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

Abstract

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.

PFKFB3 inhibition reprograms malignant pleural mesothelioma to nutrient stress-induced macropinocytosis and ER stress as independent binary adaptive responses

“…Thus PFKFB3 inhibition can trigger methuosis along with apoptosis in MPM. Remarkably, a very recent study revealed that chalcones, known to be methuosis inducers, also can adversely interfere with glucose uptake 36 . We are the first to show a metabolic connection between glycolysis with elevated macropinocytosis and impaired lysosomal function to induce methuosis and reveal a crucial role of glucose metabolism in maintaining nutrient and energy homeostasis to sustain cell survival.…”

Dysregulation of Macropinocytosis Processes in Glioblastomas May Be Exploited to Increase Intracellular Anti-Cancer Drug Levels: The Example of Temozolomide

“…Honokiol and MOMIPP have been proven to cross the BBB [35,74,75]. Although vacquinol-1 also displays an adequate BBB penetration, its systemic toxicity requires a lowering dose or local delivery [76].…”

“…Both honokiol and MOMIPP have been shown to kill drug-sensitive and -resistant glioma cells [29,77]. Recent studies pointed JNK Kinase as an important signal for both honokiol-induced effects on stem cells [78] and cytotoxic effects of indoylchalcones such as MOMIPP [75].…”

Antitumor activity of tetrandrine citrate in human glioma U87 cells in vitro and in vivo

“…It was speculated that different mechanisms of action were responsible for the differences in response to 10 µmol/l and ≥20 µmol/l TetC treatment. In the 10 µmol/l TetC-treated group, cell vacuolization was an indication of mitochondrial or endoplasmic reticulum denaturation (32), although some researchers consider this to be the result of methuosis (33). In the 20 and 40 µmol/l TetC-treated groups, cell rounding was more likely to be associated with apoptosis.…”