Cytotoxicity mechanism of α-MMC in normal liver cells through LRP1 mediated endocytosis and JNK activation

Shen, Fubing; Zhang, Min; He, Qianchuan; Zhao, Hui; Yu, Xiaoping; Yang, Shuxia; Liu, Yang; Deng, Ning; Zheng, Jie; Zhu, Lixia; Liu, Xiaolan

doi:10.1016/j.tox.2016.05.025

Cited by 20 publications

(20 citation statements)

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“…We detected elevated levels of phosphorylated JNK, but not phosphorylated p38 or ERK, in THP-1 cells incubated with α-MMC ( Figure 4A). This observation matches with previous results that α-MMC was able to activate the JNK pathway in liver cells [31]. To determine whether cytokine expression induced by α-MMC is dependent on the JNK pathway, we pre-treated THP-1 cells with JNK inhibitor SP600125 for 30 min before the addition of α-MMC.…”

Section: α-Mmc-induced Inflammatory Responses Via Jnk Pathwaysupporting

confidence: 89%

Ribosome-Inactivating Protein α-Momorcharin Derived from Edible Plant Momordica charantia Induces Inflammatory Responses by Activating the NF-kappaB and JNK Pathways

Chen

Zhu

et al. 2019

Toxins

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Alpha-momorcharin (α-MMC), a member of the ribosome-inactivating protein (RIP) family, has been found in the seeds of Momordica charantia (bitter melon). α-MMC contributes a number of pharmacological activities; however, its inflammatory properties have not been well studied. Here, we aim to determine the inflammatory responses induced by recombinant α-MMC and identify the underlying mechanisms using cell culture and animal models. Recombinant α-MMC was generated in Rosetta™(DE3)pLysS and purified by the way of nitrilotriacetic acid (NTA) chromatography. Treatment of recombinant α-MMC at 40 μg/mL exerted sub-lethal cytotoxic effect on THP-1 monocytic cells. Transcriptional profiling revealed that various genes coding for cytokines and other proinflammatory proteins were upregulated upon recombinant α-MMC treatment in THP-1 cells, including MCP-1, IL-8, IL-1β, and TNF-α. Recombinant α-MMC was shown to activate IKK/NF-κB and JNK pathways and the α-MMC-induced inflammatory gene expression could be blocked by IKKβ and JNK inhibitors. Furthermore, murine inflammatory models further demonstrated that α-MMC induced inflammatory responses in vivo. We conclude that α-MMC stimulates inflammatory responses in human monocytes by activating of IKK/NF-κB and JNK pathways, raising the possibility that consumption of α-MMC-containing food may lead to inflammatory-related diseases.

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Section: α-Mmc-induced Inflammatory Responses Via Jnk Pathwaysupporting

confidence: 89%

Ribosome-Inactivating Protein α-Momorcharin Derived from Edible Plant Momordica charantia Induces Inflammatory Responses by Activating the NF-kappaB and JNK Pathways

Chen

Zhu

et al. 2019

Toxins

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“…Against tumor cells, it was demonstrated that both alpha-momorcharin and MAP30-induced apoptosis 35 . Particularly, MAP30 caused little damage to normal cells, 38 whereas cytotoxicity to normal liver cells was observed in alpha-momorcharin 39 . Therefore, the clinical application of MAP30 was expected in cancers or protection for viral infection.…”

Section: Resultsmentioning

confidence: 99%

Draft genome sequence of bitter gourd (Momordica charantia), a vegetable and medicinal plant in tropical and subtropical regions

Urasaki

Takagi

Natsume

et al. 2016

DNA Res

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Bitter gourd (Momordica charantia) is an important vegetable and medicinal plant in tropical and subtropical regions globally. In this study, the draft genome sequence of a monoecious bitter gourd inbred line, OHB3-1, was analyzed. Through Illumina sequencing and de novo assembly, scaffolds of 285.5 Mb in length were generated, corresponding to ∼84% of the estimated genome size of bitter gourd (339 Mb). In this draft genome sequence, 45,859 protein-coding gene loci were identified, and transposable elements accounted for 15.3% of the whole genome. According to synteny mapping and phylogenetic analysis of conserved genes, bitter gourd was more related to watermelon (Citrullus lanatus) than to cucumber (Cucumis sativus) or melon (C. melo). Using RAD-seq analysis, 1507 marker loci were genotyped in an F2 progeny of two bitter gourd lines, resulting in an improved linkage map, comprising 11 linkage groups. By anchoring RAD tag markers, 255 scaffolds were assigned to the linkage map. Comparative analysis of genome sequences and predicted genes determined that putative trypsin-inhibitor and ribosome-inactivating genes were distinctive in the bitter gourd genome. These genes could characterize the bitter gourd as a medicinal plant.

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“…Previous studies have described that α‐MMC shows an inhibitory effect on human breast cancer, MDA‐MB‐231, and MCF‐7 cells, human lung adenocarcinoma epithelial A549 cells, but exhibits only slight cytotoxicity to human breast cancer MDA‐MB‐453 . Currently, a study has shown that the different degrees of cytotoxicity of α‐MMC on normal liver L02 cells, human lung epithelial cell line BEAS‐2B cells, and embryonic kidney cell line AD293 cells are related to their amount of low‐density lipoprotein receptor‐related protein 1 (LRP 1) receptor density on the cell surface , suggesting that the application of α‐MMC is limited by the distribution pattern of the LRP1 on certain cell surface, which is the key factor affecting the amount of the α‐MMC in the cells. CPPs have the potential to overcome this limitation and are a promising tool to transport RIPs into cancer cells .…”

Section: Discussionmentioning

confidence: 99%

Effectively enhancing cytotoxic and apoptotic effects of alpha‐momorcharin by integrating a heparin‐binding peptide

Tan

Cao

et al. 2017

Biotech and App Biochem

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Alpha-momorcharin (α-MMC), a type I ribosome-inactivating protein, has attracted a great deal of attention because of its antitumor activity. However, the cytotoxicity of α-MMC is limited due to insufficient cellular internalization in cancer cells. To enhance the cytotoxicity of α-MMC, a heparin-binding domain derived from heparin-binding epidermal growth factor (named heparin-binding peptide [HBP]) was used as a cell-penetrating peptide and fused to the C-terminus of α-MMC. This novel α-MMC-HBP fusion protein was expressed and purified with a Ni -resin. The N-glycosidase activity and DNase activity assay indicated that the introduction of HBP did not interfere with the intrinsic bioactivities of α-MMC. HBP was able to efficiently carry α-MMC into the tested cancer cells and significantly enhance the cytotoxic effects of α-MMC in a dose-dependent manner. This enhanced cytotoxic ability occurred due to the higher level of cell apoptosis induced by α-MMC-HBP, which was demonstrated in western blot analysis in which α-MMC-HBP triggered caspase 8, caspase 9, casapase 3, and PARP more intensely than α-MMC alone. α-MMC-HBP led to an upregulation of cleaved PARP and an increase in the Bax/Bcl-2 ratio. Our study provided a new practical way to greatly improve the antitumor activity of α-MMC, which could significantly expand the pharmaceutical applications of α-MMC.

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Cytotoxicity mechanism of α-MMC in normal liver cells through LRP1 mediated endocytosis and JNK activation

Cited by 20 publications

References 50 publications

Ribosome-Inactivating Protein α-Momorcharin Derived from Edible Plant Momordica charantia Induces Inflammatory Responses by Activating the NF-kappaB and JNK Pathways

Ribosome-Inactivating Protein α-Momorcharin Derived from Edible Plant Momordica charantia Induces Inflammatory Responses by Activating the NF-kappaB and JNK Pathways

Draft genome sequence of bitter gourd (Momordica charantia), a vegetable and medicinal plant in tropical and subtropical regions

Effectively enhancing cytotoxic and apoptotic effects of alpha‐momorcharin by integrating a heparin‐binding peptide

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