Elaiophylin triggers paraptosis and preferentially kills ovarian cancer drug-resistant cells by inducing MAPK hyperactivation

Abstract

Finely tuned mitogen-activated protein kinase (MAPK) signaling is important for cancer cell survival. Perturbations that push cells out of the MAPK fitness zone result in cell death. Previously, in a screen of the North China Pharmaceutical Group Corporation’s pure compound library of microbial origin, we identified elaiophylin as an autophagy inhibitor. Here, we demonstrated a new role for elaiophylin in inducing excessive endoplasmic reticulum (ER) stress, ER-derived cytoplasmic vacuolization, and consequent paraptosis by hyperactivating the MAPK pathway in multiple cancer cells. Genome-wide CRISPR/Cas9 knockout library screening identified SHP2, an upstream intermediary of the MAPK pathway, as a critical target in elaiophylin-induced paraptosis. The cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) assay further confirmed the direct binding between the SHP2 and elaiophylin. Inhibition of the SHP2/SOS1/MAPK pathway through SHP2 knockdown or pharmacological inhibitors distinctly attenuated elaiophylin-induced paraptosis and autophagy inhibition. Interestingly, elaiophylin markedly increased the already-elevated MAPK levels and preferentially killed drug-resistant cells with enhanced basal MAPK levels. Elaiophylin overcame drug resistance by triggering paraptosis in multiple tumor-bearing mouse models resistant to platinum, taxane, or PARPi, suggesting that elaiophylin might offer a reasonable therapeutic strategy for refractory ovarian cancer.

Paraptotic Cell Death as an Unprecedented Mode of Action Observed for New Bipyridine-Silver(I) Compounds Bearing Phosphane Coligands

“…Accordingly, also in the case of the silver drugs, the addition of the pan-caspase inhibitor z-VAD-FMK had no impact on the ER-derived vacuoles (Figure S45) or anticancer activity (Figure S46). Another hallmark of paraptosis is the dependence on the mitogen-activated protein kinase (MAPK) signaling. , Comparable to other paraptosis inducers, also in the case of this drug panel, the MAPK inhibitor U0126 had protective effects (Figure ). Noteworthily, the effect was stronger in MES-OV cells for 4 and 7 followed by 1 .…”

Apoptosis and Paraptosis Induced by Disulfiram-Loaded Ca2+/Cu2+ Dual-Ions Nano Trap for Breast Cancer Treatment

“…Paraptosis-based programmed cell death is featured by typical cytoplasmic vacuolation, which originates from the dilation of mitochondria and/or ER. 54 Afterward, DM-CaCO 3 @L-PEGmediated paraptosis was investigated by Western blot and quantitative reverse transcription polymerase chain reaction (RT-PCR). DM-CaCO 3 @L-PEG NPs could decrease the expression of Alix protein, a negative regulator for paraptosis, which had the advantage of activating paraptosis of tumor cells.…”

“…52 Meanwhile, paraptosis is usually mediated by the MAPKs pathway. 54 Furthermore, gene ontology (GO) analysis was also performed to investigate the biological functions of related mRNAs and the corresponding influence pathways (Figure 7c,d). GO analysis among the DM-CaCO 3 @L-PEG-treated group and control group implied a strong correlation of DM-CaCO 3 @L-PEG NPs with cell cycle process, vacuolar part, proteasome complex, and ubiquitin-like protein ligase binding, which performs a significant relationship with paraptosis.…”

“…Furthermore, the treated cells were also stained with Mitro-Tracker Red and ER-Tracker Blue to further investigate the DM-CaCO 3 @L-PEG-mediated morphology change, in which a visualized bubble could be observed on the surface of mitochondria and ER surface (Figure b). Paraptosis-based programmed cell death is featured by typical cytoplasmic vacuolation, which originates from the dilation of mitochondria and/or ER . Afterward, DM-CaCO 3 @L-PEG-mediated paraptosis was investigated by Western blot and quantitative reverse transcription polymerase chain reaction (RT-PCR).…”

Possible correlated signaling pathways with chronic urate nephropathy: A review

“…MAPK can be stimulated by a variety of extracellular stimuli (growth factors, [96] cytokines, [97] lipotoxicity, [98] rate threshold [99] ) and activate serine-threonine protein kinases to transduce cell [101] p38, [102] JNK, [103] ERK5 [104] ) through protein factors (RAS, [105] MAP3K, [106] MAP2K, [107] MAPK [108] ) which in turn regulate cell proliferation, [109] differentiation, [110] inflammation-mediated [111] and apoptosis. [112] The pathological basis of HN is that excessive deposition of urate induces phenotypic changes in renal tubular epithelial cell injury. Luo [113] found that the deposition of UA single crystal can induce the activation of MAPK.…”