M-COPA, a Golgi Disruptor, Inhibits Cell Surface Expression of MET Protein and Exhibits Antitumor Activity against MET-Addicted Gastric Cancers

Ohashi, Yoshimi; Okamura, Mutsumi; Hirosawa, Asaka; Tamaki, Naomi; Akatsuka, Akinobu; Wu, Kuang‐Chong; Choi, Hyeong Wook; Yoshimatsu, Kentaro; Shiina, Isamu; Yamori, Takao; Dan, Shingo

doi:10.1158/0008-5472.can-15-2220

Cited by 27 publications

(26 citation statements)

References 45 publications

(50 reference statements)

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“…Recent studies showed that M-COPA has an anti-cancer effect in Met tyrosine kinase-addicted cancers in vivo through inhibition of the trafficking of the receptor to the PM [31–33]. Therefore, we investigated the effect of M-COPA on oncogenic Kit signalling in neoplastic mast cells.…”

Section: Resultsmentioning

confidence: 99%

“…However, BFA has less stability in vivo while the others exhibit weaker inhibition of cell growth, and their development as drugs has not progressed. On the other hand, M-COPA had an anti-cancer effect in vivo experiments using breast cancer or gastric cancer xenograft models [32,33], and it is now considered a novel anticancer drug candidate. Together with the fact that M-COPA suppressed imatinib-resistant Kit signalling, inhibition of receptor trafficking is a promising approach for the treatment of cancers bearing a resistant mutation to targeting therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies showed that M-COPA blocks the trafficking of Met receptor kinase along the secretory pathway to the PM, resulting in suppression of receptor-ligand binding [33,34]. Thus, M-COPA has an anti-tumour effect in vivo .…”

Section: Introductionmentioning

confidence: 99%

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M-COPA suppresses endolysosomal Kit-Akt oncogenic signalling through inhibiting the secretory pathway in neoplastic mast cells

et al. 2017

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Gain-of-function mutations in Kit receptor tyrosine kinase result in the development of a variety of cancers, such as mast cell tumours, gastrointestinal stromal tumours (GISTs), acute myeloid leukemia, and melanomas. The drug imatinib, a selective inhibitor of Kit, is used for treatment of mutant Kit-positive cancers. However, mutations in the Kit kinase domain, which are frequently found in neoplastic mast cells, confer an imatinib resistance, and cancers expressing the mutants can proliferate in the presence of imatinib. Recently, we showed that in neoplastic mast cells that endogenously express an imatinib-resistant Kit mutant, Kit causes oncogenic activation of the phosphatidylinositol 3-kinase-Akt (PI3K-Akt) pathway and the signal transducer and activator of transcription 5 (STAT5) but only on endolysosomes and on the endoplasmic reticulum (ER), respectively. Here, we show a strategy for inhibition of the Kit-PI3K-Akt pathway in neoplastic mast cells by M-COPA (2-methylcoprophilinamide), an inhibitor of this secretory pathway. In M-COPA-treated cells, Kit localization in the ER is significantly increased, whereas endolysosomal Kit disappears, indicating that M-COPA blocks the biosynthetic transport of Kit from the ER. The drug greatly inhibits oncogenic Akt activation without affecting the association of Kit with PI3K, indicating that ER-localized Kit-PI3K complex is unable to activate Akt. Importantly, M-COPA but not imatinib suppresses neoplastic mast cell proliferation through inhibiting anti-apoptotic Akt activation. Results of our M-COPA treatment assay show that Kit can activate Erk not only on the ER but also on other compartments. Furthermore, Tyr568/570, Tyr703, Tyr721, and Tyr936 in Kit are phosphorylated on the ER, indicating that these five tyrosine residues are all phosphorylated before mutant Kit reaches the plasma membrane (PM). Our study provides evidence that Kit is tyrosine-phosphorylated soon after synthesis on the ER but is unable to activate Akt and also demonstrates that M-COPA is efficacious for growth suppression of neoplastic mast cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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M-COPA suppresses endolysosomal Kit-Akt oncogenic signalling through inhibiting the secretory pathway in neoplastic mast cells

et al. 2017

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“…Other strategies to impair the ER-Golgi network are being currently pursued as anti-cancer therapy. For example, the M-COPA (2-methylcoprophilinamide) compound, inhibiting Arf1 (ADP ribosylation factor 1) involved in COPI and clathrin-coated transport vesicles, has been shown to disrupt the Golgi apparatus and RTK translocation to the membrane, to have antitumor effects against MET-addicted gastric cancers, and to overcome TKI resistance in EGFR-mutated non-small-cell lung carcinoma [124,125].…”

Section: Validation Of Noa Targetsmentioning

confidence: 99%

Targeting Non-Oncogene Addiction: Focus on Thyroid Cancer

Anania

Marco

Mazzoni

et al. 2020

Cancers

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Thyroid carcinoma (TC) is the most common malignancy of endocrine organs with an increasing incidence in industrialized countries. The majority of TC are characterized by a good prognosis, even though cases with aggressive forms not cured by standard therapies are also present. Moreover, target therapies have led to low rates of partial response and prompted the emergence of resistance, indicating that new therapies are needed. In this review, we summarize current literature about the non-oncogene addiction (NOA) concept, which indicates that cancer cells, at variance with normal cells, rely on the activity of genes, usually not mutated or aberrantly expressed, essential for coping with the transformed phenotype. We highlight the potential of non-oncogenes as a point of intervention for cancer therapy in general, and present evidence for new putative non-oncogenes that are essential for TC survival and that may constitute attractive new therapeutic targets.

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“…1A) (Ohashi et al 2012). Very recently, it has been reported that M-COPA exerts antitumor activity by inhibiting cell surface expression of MET protein in MET-addicted gastric cancers (Ohashi et al 2016). In this study, we explored the action of M-COPA as a novel suppressor of apoptosis in Stx-treated cells.…”

Section: Introductionmentioning

confidence: 99%

M‐COPA, a novel Golgi system disruptor, suppresses apoptosis induced by Shiga toxin

et al. 2016

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Shiga toxin (Stx) is a main virulence factor of Stx‐producing Escherichia coli (STEC) that contributes to diarrhea and hemorrhagic colitis and occasionally to fatal systemic complications. Therefore, the development of an antidote to neutralize Stx toxicity is urgently needed. After internalization into cells, Stx is transferred to the Golgi apparatus via a retrograde vesicular transport system. We report here that 2‐methylcoprophilinamide (M‐COPA), a compound that induces disassembly of the Golgi apparatus by inactivating ADP‐ribosylation factor 1 (Arf1), suppresses Stx‐induced apoptosis. M‐COPA inhibited transport of Stx from the plasma membrane to the Golgi apparatus and suppressed degradation of anti‐apoptotic proteins and the activation of caspases. These findings suggest that inhibition of Stx retrograde transport by M‐COPA could be a novel approach to suppress Stx toxicity.

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M-COPA, a Golgi Disruptor, Inhibits Cell Surface Expression of MET Protein and Exhibits Antitumor Activity against MET-Addicted Gastric Cancers

Cited by 27 publications

References 45 publications

M-COPA suppresses endolysosomal Kit-Akt oncogenic signalling through inhibiting the secretory pathway in neoplastic mast cells

M-COPA suppresses endolysosomal Kit-Akt oncogenic signalling through inhibiting the secretory pathway in neoplastic mast cells

Targeting Non-Oncogene Addiction: Focus on Thyroid Cancer

M‐COPA, a novel Golgi system disruptor, suppresses apoptosis induced by Shiga toxin

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