Inhibition of c-Met downregulates TIGAR expression and reduces NADPH production leading to cell death

Lui, Vivian Wai Yan; Wong, Ella Lai‐Ming; Ho, Kwok W.; Ng, Patrick Kwok Shing; Lau, Condon; Tsui, Stephen Kwok‐Wing; Tsang, Chi-Man; Tsao, Sai‐Wah; Cheng, Suk Hang; Ng, Margaret H.L.; Ng, Yuen Keng; Lam, Emily Kai Yee; Hong, Bo; Lo, Kwok Wai; Mok, Tony; Chan, Anthony T.C.; Mills, Gordon B.

doi:10.1038/onc.2010.490

Cited by 55 publications

(49 citation statements)

References 20 publications

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“…Taken together, our data suggest that TIGAR is induced in response to ROS, and previous work has shown that TIGAR can function to provide antioxidant defense (Bensaad et al 2006(Bensaad et al , 2009Lui et al 2011;Wanka et al 2012;Yin et al 2012;Cheung et al 2013). Normal and tumor intestinal crypts derived from constitutive TIGAR-null mice grew less well in 3D cultures, and these could be rescued with antioxidants such as N-acetyl L-cysteine (NAC) (Cheung et al 2013).…”

Section: Tigar Supports Intestinal Cell Growth By Limiting Damaging Rossupporting

confidence: 63%

“…The first focuses on TIGAR, a protein that can control glucose metabolism and helps to maintain NADPH levels to regenerate glutathione (GSH), a key intracellular antioxidant. Loss of TIGAR expression leads to increased ROS, and while this is not obviously detrimental to normal growth and development, in most model systems, this results in defects in both proliferation and survival following stress (Bensaad et al 2006(Bensaad et al , 2009Lui et al 2011;Wanka et al 2012;Yin et al 2012). In the mouse intestine, loss of TIGAR can decrease the proliferation that accompanies tissue regeneration after genotoxic stress and limit the hyperproliferation seen in Wnt-driven adenoma through the failure to limit ROS (Cheung et al 2013).…”

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confidence: 99%

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Opposing effects of TIGAR- and RAC1-derived ROS on Wnt-driven proliferation in the mouse intestine

et al. 2015

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Reactive oxygen species (ROS) participate in numerous cell responses, including proliferation, DNA damage, and cell death. Based on these disparate activities, both promotion and inhibition of ROS have been proposed for cancer therapy. However, how the ROS response is determined is not clear. We examined the activities of ROS in a model of Apc deletion, where loss of the Wnt target gene Myc both rescues APC loss and prevents ROS accumulation. Following APC loss, Myc has been shown to up-regulate RAC1 to promote proliferative ROS through NADPH oxidase (NOX). However, APC loss also increased the expression of TIGAR, which functions to limit ROS. To explore this paradox, we used three-dimensional (3D) cultures and in vivo models to show that deletion of TIGAR increased ROS damage and inhibited proliferation. These responses were suppressed by limiting damaging ROS but enhanced by lowering proproliferative NOX-derived ROS. Despite having opposing effects on ROS levels, loss of TIGAR and RAC1 cooperated to suppress intestinal proliferation following APC loss. Our results indicate that the pro-and anti-proliferative effects of ROS can be independently modulated in the same cell, with two key targets in the Wnt pathway functioning to integrate the different ROS signals for optimal cell proliferation.

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Section: Tigar Supports Intestinal Cell Growth By Limiting Damaging Rossupporting

confidence: 63%

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confidence: 99%

Opposing effects of TIGAR- and RAC1-derived ROS on Wnt-driven proliferation in the mouse intestine

et al. 2015

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“…Alternatively, MUC1-C could contribute to stability of the TIGAR protein, such that inhibition of MUC1-C promotes TIGAR turnover. Inhibition of the MET receptor tyrosine kinase also down-regulates TIGAR expression; 31 however, there is presently nothing known about the mechanisms responsible for the regulation of TIGAR at the transcriptional or posttranscriptional levels. Given the finding that inhibition of MUC1-C increases ROS levels, the present studies examined whether oxidative stress contributes to the down-regulation of TIGAR expression.…”

Section: Muc1-c Regulates Tigar Expression In Multiple Myeloma Cellsmentioning

confidence: 99%

Inhibition of the MUC1-C oncoprotein induces multiple myeloma cell death by down-regulating TIGAR expression and depleting NADPH

Kosugi

Küfe

2012

Blood

107

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The MUC1-C oncoprotein is aberrantly expressed in most multiple myeloma cells. However, the functional significance of MUC1-C expression in multiple myeloma is not known. The present studies demonstrate that treatment of multiple myeloma cells with a MUC1-C inhibitor is associated with increases in reactive oxygen species (ROS), oxidation of mitochondrial cardiolipin, and loss of the mitochondrial transmembrane potential. The MUC1-C inhibitor-induced increases in ROS were also associated with downregulation of the p53-inducible regulator of glycolysis and apoptosis (TIGAR). In concert with the decrease in TIGAR expression, which regulates the pentose phosphate pathway, treatment with the MUC1-C inhibitor reduced production of NADPH, and in turn glutathione (GSH) levels. TIGAR protects against oxidative stress-induced apoptosis. The suppression of TIGAR and NADPH levels thus contributed to ROS-mediated late apoptosis/necrosis of multiple myeloma cells. These IntroductionMultiple myeloma is an incurable hematologic disorder that is characterized by the clonal proliferation of malignant plasma cells. Targeted agents, such as the proteosome inhibitor, bortezomib, and the immunomodulatory agent lenalidamide, have extended overall survival for patients with multiple myeloma. 1 However, invariably, patients eventually relapse and succumb to this disease, emphasizing the need for additional therapeutic targets.Mucin 1 (MUC1) is a heterodimeric protein that is aberrantly expressed in most multiple myeloma cell lines and primary patient samples. [2][3][4][5][6][7][8] The extracellular MUC1 N-terminal subunit (MUC1-N) contains glycosylated tandem repeats that are a characteristic of mucin family members. 9 MUC1-N forms a complex with the transmembrane MUC1 C-terminal subunit (MUC1-C) at the cell surface. 9 MUC1-C consists of a 58 amino acid extracellular domain that associates with galectin-3, 10 and a 72 amino acid cytoplasmic domain that interacts with diverse effectors that have been linked to transformation. 9 In this regard, MUC1-C expression is sufficient to induce anchorage-independent growth and tumorigenicity. 11,12 In addition to localization in the cell membrane, MUC1-C is detectable in the cytoplasm of multiple myeloma cells and is targeted to the nucleus. 13 Of functional relevance, MUC1-C expression in multiple myeloma cells is associated with activation of the Wnt/␤-catenin and NF-B RelA pathways. 8 Moreover, silencing MUC1-C in multiple myeloma cells results in slowing of proliferation and enhanced sensitivity to apoptosis, and loss of self-renewal in the response to melphalan and dexamethasone. 8 These findings thus provided support for the involvement of MUC1-C in multiple myeloma cell growth and survival.The MUC1-C cytoplasmic domain contains a CQC motif that is necessary for its oligomerization and thereby its nuclear localization. 14 Based on these findings, cell-penetrating peptide drugs were developed to inhibit MUC1-C oligomerization and its oncogenic function. 15 The peptide inhibitors contain t...

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“…[15][16][17][18] Over-expression of MET has also been detected in cell lines established from Asian-prevalent head and neck cancer, nasopharyngeal cancer, pediatric tumors including osteogenic sarcoma and neuroblastoma, and hematopoietic malignancies including multiple myeloma and adult T-cell leukemia. [19][20][21][22][23] Constitutive MET activation due to MET amplification and/or MET mutation has been found to be a driver of proliferation and survival. MET expression correlates with an aggressive phenotype and poor prognosis.…”

Section: Met and Cancermentioning

confidence: 99%

Receptor Tyrosine Kinases and Targeted Cancer Therapeutics

Takeuchi

Ito

2011

Biological & Pharmaceutical Bulletin

141

113

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The majority of growth factor receptors are composed of extracellular, transmembrane, and cytoplasmic tyrosine kinase (TK) domains. Receptor tyrosine kinase (RTK) activation regulates many key processes including cell growth and survival. However, dysregulation of RTK has been found in a wide range of cancers, and it has been shown to correlate with the development and progression of numerous cancers. Therefore, RTK has become an attractive therapeutic target. One way to effectively block signaling from RTK is inhibition of its catalytic activity with small-molecule inhibitors. Low-molecular-weight TK inhibitors (TKIs), such as imatinib, targeting tumors with mutant c-Kit, and gefitinib, targeting non-small cell lung cancer with mutant epidermal growth factor receptor (EGFR), have received marketing approval in Japan. MET, fibroblast growth factor receptor (FGFR), and insulin-like growth factor-I receptor (IGF-IR) are frequently genetically altered in advanced cancers. TKIs of these receptors have not yet appeared on the market, but many anticancer drug candidates are currently undergoing clinical trials. Most of these TKIs were designed to compete with ATP at the ATP-binding site within the TK domain. This review will focus on small-molecule TKIs targeting MET, FGFR, and IGF-IR and discuss the merits and demerits of two types of agents, i.e., those with only one or a few targets and those directed at multiple targets. Targeting agents specifically inhibiting the target kinase were previously searched for based on the hypothesis that a narrow target window might reduce unexpected side effects, but agents with multiple targets have been recently developed to overcome tumors resistant against a single-targeting agent.

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Inhibition of c-Met downregulates TIGAR expression and reduces NADPH production leading to cell death

Cited by 55 publications

References 20 publications

Opposing effects of TIGAR- and RAC1-derived ROS on Wnt-driven proliferation in the mouse intestine

Opposing effects of TIGAR- and RAC1-derived ROS on Wnt-driven proliferation in the mouse intestine

Inhibition of the MUC1-C oncoprotein induces multiple myeloma cell death by down-regulating TIGAR expression and depleting NADPH

Receptor Tyrosine Kinases and Targeted Cancer Therapeutics

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