STI571 (Glivec) induces cell death in the gastrointestinal stromal tumor cell line, GIST-T1, via endoplasmic reticulum stress response

Nakatani, Hajime; Araki, Keijiro; Jin, Tengchuan; Kobayashi, Mariko; Sugimoto, Takeki; Akimori, Toyokazu; Namikawa, Tsutomu; Nakano, Takumi; Okabayashi, Takehiro; Hokimoto, Norihiro; Kitagawa, Hiroyuki; Taguchi, Takahiro

doi:10.3892/ijmm.17.5.893

Cited by 10 publications

(9 citation statements)

References 17 publications

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“…As expected, 2DG caused ER stress and elicited the unfolded protein response (UPR). To our surprise, IM did not induce ER-stress or UPR, which differs from previous findings by Nakatani et al, who demonstrated induction of GRP78 by imatinib albeit at a higher concentration of ~2μM [ 33 ]. In combined treatment, ER-stress and the UPR could be important complementary effects of 2DG, reducing TKI-induced quiescence and promoting the apoptotic response.…”

Section: Discussioncontrasting

confidence: 99%

Inhibition of KIT-Glycosylation by 2-Deoxyglucose Abrogates KIT-Signaling and Combination with ABT-263 Synergistically Induces Apoptosis in Gastrointestinal Stromal Tumor

et al. 2015

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Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) is frequently used for visualizing gastrointestinal stromal tumors (GIST), which are highly glucose-avid tumors. Dramatic metabolic responses following imatinib treatment indicate a high, KIT-dependent glucose turnover which has been particularly helpful for predicting tumor response to imatinib. The glucose analogue 2-deoxyglucose (2DG) inhibits glucose metabolism in cancer cells that depend on aerobic glycolysis for ATP production. We show that 2DG inhibits proliferation in both imatinib-sensitive and imatinib-resistant GIST cell lines at levels that can be achieved clinically. KIT-negative GIST48B have 3-14-fold higher IC50 levels than KIT-positive GIST cells indicating that oncogenic KIT may sensitize cells to 2DG. GIST sensitivity to 2DG is increased in low-glucose media (110mg/dl). 2DG leads to dose- and glucose dependent inhibition of KIT glycosylation with resultant reduction of membrane-bound KIT, inhibition of KIT-phosphorylation and inactivation of KIT-dependent signaling intermediates. In contrast to imatinib, 2DG caused ER-stress and elicited the unfolded protein response (UPR). Mannose but not pyruvate rescued GIST cells from 2DG-induced growth arrest, suggesting that loss of KIT integrity is the predominant effect of 2DG in GIST. Additive anti-tumoral effects were seen with imatinib and BH3-mimetics. Our data provide the first evidence that modulation of the glucose-metabolism by 2DG may have a disease-specific effect and may be therapeutically useful in GIST.

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Section: Discussioncontrasting

confidence: 99%

Inhibition of KIT-Glycosylation by 2-Deoxyglucose Abrogates KIT-Signaling and Combination with ABT-263 Synergistically Induces Apoptosis in Gastrointestinal Stromal Tumor

et al. 2015

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“…Other studies documented expression of a 50-kD BASIC RESEARCH www.jasn.org caspase-12 in human promyelocytic leukemia cells (HL-60) 48 and a 60-kD caspase-12 in human gastrointestinal stromal tumors (STI571). 45 It is not clear how a 52-or 60-kD caspase-12 protein can be expressed in the presence of a stop codon; however, these studies raise the possibility that the 52-or 60-kD pro-caspase-12 could be aberrantly expressed in cells undergoing pathologic changes.…”

Section: Discussionmentioning

confidence: 83%

Reactive Oxygen Species Promote Caspase-12 Expression and Tubular Apoptosis in Diabetic Nephropathy

Brezniceanu¹,

Lau²,

Godin³

et al. 2010

Journal of the American Society of Nephrology

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Apoptosis of tubular epithelial cells contributes to the tubular atrophy that accompanies diabetic nephropathy. Reactive oxygen species (ROS) promote tubular apoptosis, but the mechanisms by which this occurs are incompletely understood. Here, we sought proapoptotic genes that ROS differentially upregulate in renal proximal tubular cells of diabetic (db/db) mice. We performed microarray analysis using total RNA from freshly isolated renal proximal tubules of nondiabetic, diabetic, and diabetic transgenic mice overexpressing catalase in the proximal tubule (thereby attenuating ROS). We observed greater expression of caspase-12 in the proximal tubules of the diabetic mice compared with the nondiabetic and diabetic transgenic mice. Quantitative PCR and immunohistochemistry confirmed the enhanced expression of caspase-12, as well as members of the endoplasmic reticulum stress-induced apoptotic pathway. Ex vivo, albumin induced caspase-12 activity and expression (protein and mRNA) and mRNA expression of the CCAT/enhancer-binding protein homologous protein in freshly isolated wildtype proximal tubules but not in catalase-overexpressing proximal tubules. In vitro, albumin stimulated activity of both caspase-12 and caspase-3 as well as expression of caspase-12 and CCAT/enhancerbinding protein homologous protein in a human proximal tubule cell line (HK-2). The free radical scavenger tiron inhibited these effects. Furthermore, knockdown of caspase-12 with small interfering RNA reduced albumin-induced apoptosis in HK-2 cells. Taken together, these studies demonstrate that albuminuria may induce tubular apoptosis through generation of ROS and the subsequent expression and activation of endoplasmic reticulum stress genes in the diabetic kidney.

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“…We and others have previously found that imatinib‐induced apoptosis occurs in GIST cells and human tumor tissue (McAuliffe et al., 2009; Trent et al., 2006). In imatinib‐sensitive GIST cells, apoptosis occurs partly through the BIM upregulation and its subsequent antagonism of pro‐survival Bcl‐2 proteins, but also through a variety of other intracellular stresses, including H2AX‐mediated transcriptional arrest and ER stress, which also activate the intrinsic pathway of apoptosis (Liu et al., 2007; Nakatani et al., 2006). However, apoptosis is not the only effect of imatinib treatment, even in sensitive models.…”

Section: Discussionmentioning

confidence: 99%

Synergistic induction of apoptosis by the Bcl‐2 inhibitor ABT‐737 and imatinib mesylate in gastrointestinal stromal tumor cells

et al. 2010

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STI571 (Glivec) induces cell death in the gastrointestinal stromal tumor cell line, GIST-T1, via endoplasmic reticulum stress response

Cited by 10 publications

References 17 publications

Inhibition of KIT-Glycosylation by 2-Deoxyglucose Abrogates KIT-Signaling and Combination with ABT-263 Synergistically Induces Apoptosis in Gastrointestinal Stromal Tumor

Inhibition of KIT-Glycosylation by 2-Deoxyglucose Abrogates KIT-Signaling and Combination with ABT-263 Synergistically Induces Apoptosis in Gastrointestinal Stromal Tumor

Reactive Oxygen Species Promote Caspase-12 Expression and Tubular Apoptosis in Diabetic Nephropathy

Synergistic induction of apoptosis by the Bcl‐2 inhibitor ABT‐737 and imatinib mesylate in gastrointestinal stromal tumor cells

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