Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas

Lu, Yuan; Choi, Kihang; Khosla, Chaitan; Zheng, X.F. Steven; Higashikubo, Ryuji; Chicoine, Michael R.; Rich, Keith M.

doi:10.1158/1535-7163.mct-04-0328

Cited by 83 publications

(88 citation statements)

References 33 publications

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“…In the current study, we showed that TGase 2 inhibition promoted sensitivity to the chemotherapeutic drug doxorubicin and that this correlated with NF-nB inactivation, indicating that TGase 2 inhibition in breast cancer cells is an effective approach to promoting chemosensitivity. This is supported by the observation that the combined use of TGase inhibitors and chemotherapeutic agents decreased the size of glioblastoma tumors by 50% compared with treatment with chemotherapeutic agents (40). Given that expressions of TGase 2 and NF-nB can be induced by chemotherapeutic agents, this raises the possibility that TGase 2 inhibition in combination with NF-nB inhibition may result in increased sensitivity to chemotherapeutic drugs and represent a potentially useful therapeutic approach to the treatment of certain cancers (25,41).…”

Section: Discussionmentioning

confidence: 90%

Reversal of Drug Resistance in Breast Cancer Cells by Transglutaminase 2 Inhibition and Nuclear Factor-κB Inactivation

et al. 2006

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Induction of transglutaminase 2 (TGase 2) by epidermal growth factor (EGF) in human breast cancer cells increases their oncogenic potential and chemoresistance. The role of TGase 2 in the development of these tumor-related phenotypes remains to be elucidated, but it has been shown that expression of a dominant-negative form of TGase 2 reverses EGF-mediated chemoresistance in breast cancer cells. We examined several different breast cancer cell lines, representing both EGF receptor (EGFR)-positive and EGFR-negative breast cancers, and found that doxorubicin-resistant cells had a higher level of TGase 2 compared with doxorubicin-sensitive cells independent of the EGFR expression level. TGase 2 inhibition increased the chemosensitivity of drug-resistant cells, concomitant with a decrease in nuclear factor-KB (NF-KB) activity. Increasing the level of TGase 2 in drugsensitive cells by transient transfection reduced the level of inhibitory subunit A of NF-KB (IKBA) and increased NF-KB activity in these cells. Inhibition of TGase 2 in drug-resistant cells by RNA interference increased the levels of IKBA, and this correlated with a shift in the accumulation of NF-KB from the nucleus to the cytosol. We recently showed that TGase 2 activated NF-KB through polymerization and depletion of free IKBA during inflammation. Therefore, increased expression of TGase 2 and subsequent activation of NF-KB may contribute to drug resistance in breast cancer cells independently of EGF signaling. (Cancer Res 2006; 66(22): 10936-43)

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Section: Discussionmentioning

confidence: 90%

Reversal of Drug Resistance in Breast Cancer Cells by Transglutaminase 2 Inhibition and Nuclear Factor-κB Inactivation

et al. 2006

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“…To our knowledge, this is the first evidence that a transglutaminase inhibitor affects CREB phosphorylation in cancer cells. As CREB regulates the transcription of many oncogenic proteins, this mechanism may be implicated in the anti-cancer properties of TG2 inhibitors (27,43).…”

Section: Discussionmentioning

confidence: 99%

“…To investigate whether the enzymatic activity of TG2 plays a role in regulating MMP-2 expression and function, we used KCC009, a dihydroisoxazole TG2 inhibitor (27). Treatment of ovarian cancer cells with KCC009 decreased the expression (Fig.…”

Section: Tg2 Modulates the Expression Of Mmp-2 And Other Metastasis-rmentioning

confidence: 99%

Tissue Transglutaminase Regulates Matrix Metalloproteinase-2 in Ovarian Cancer by Modulating cAMP-response Element-binding Protein Activity

Satpathy

Shao

Emerson³

et al. 2009

Journal of Biological Chemistry

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Tissue transglutaminase 2 (TG2) is overexpressed in epithelial ovarian cancer (EOC) and promotes intraperitoneal metastasis. How TG2 facilitates the spread of EOC is unknown. Here, we show that TG2 regulates the expression and function of matrix metalloproteinase-2 (MMP-2), a critical mediator of tissue invasiveness. TG2 knockdown down-regulates MMP-2 protein and mRNA expression in SKOV3, IGROV-1, MDA-MB-436, and PC-3 cancer cells. TG2 knockdown or inhibition of TG2 activity using KCC009 decreases MMP-2 gelatinase activity in cancer cells. MMP-2 expression and function are regulated by TG2 at transcriptional level, as demonstrated by quantitative PCR and reporter assays. We used bioinformatics and chromatin immunoprecipitation to identify a CREB binding site in the MMP-2 promoter. Binding of CREB to the MMP-2 promoter was diminished in cells that expressed decreased TG2 levels. TG2 knockdown decreased CREB phosphorylation, and CREB knockdown decreased MMP-2 expression. The effect of TG2 on CREB activity and MMP-2 transcription is mediated by TG2-dependent degradation of protein phosphatase 2 (PP2A-␣). We show that PP2A-␣ complexes with and is targeted for degradation by TG2. In addition to their related in vitro expression levels, TG2 and MMP-2 expression were significantly correlated in vivo, as shown by concordant immunostaining in peritoneal xenografts and in human ovarian tumors. The capacity of TG2 to regulate MMP-2 expression in vitro and in vivo identifies a mechanism that may facilitate tissue invasion and the spread of EOC. The demonstration that TG2 induced degradation of PP2A-␣ activates CREB, and thereby increases MMP-2 transcription, provides novel mechanistic insight into the prometastatic function of TG2.Transglutaminase 2 (TG2), 2 an enzyme overexpressed in epithelial malignancies (1, 2), cross-links proteins by acyltransfer between glutamine and lysine residues and participates in Ca 2ϩ -dependent post-translational protein modification by incorporating polyamines into peptide chains (3). We recently reported that TG2 is up-regulated in transformed ovarian epithelial cells and tumors compared with normal cells, and facilitates peritoneal dissemination of EOC cells (1, 4). TG2 has multiple functions. It strengthens integrin-dependent cell adhesion, modulates intracellular signaling, and remodels the extracellular matrix through protein cross-linking (5). To understand the involvement of TG2 in the process of intraperitoneal metastasis, we investigated its involvement in the regulation of proteins known to facilitate tumor invasion and spread.Matrix metalloproteinases (MMPs) are a family of secreted proteins that remodel and digest the extracellular matrix. In the context of malignancy, MMPs play a prominent role in metastasis and angiogenesis (6), because degradation of the extracellular matrix in the immediate vicinity of a tumor niche facilitates cancer cell invasion and escape from the primary tumor site (7,8). Regulation of MMP activity occurs at different levels (9). MMPs are secreted as pro...

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“…However, cystamine treatment of Huntington mice decreased the number and size of aggregates and delayed the neuropathological sequela [22], albeit cystamine has additional non-TG2-related effects such as caspase inhibition [31]. In contrast, TG inhibitors, including KCC009 and MDC, have pro-apoptotic effects that enhance chemosensitivity of glioblastomas [32].…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic transglutaminase inhibition attenuates drug‐primed liver hypertrophy but not Mallory body formation

Strnad¹,

Siegel²,

Toivola³

et al. 2006

FEBS Letters

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Mallory bodies (MBs) are characteristic of several liver disorders, and consist primarily of keratins with transglutaminase-generated keratin crosslinks. We tested the effect of the transglutaminase-2 (TG2) inhibitor KCC009 on MB formation in a mouse model fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). KCC009 decreased DDC-induced liver enlargement without affecting MB formation or extent of liver injury. TG2 protein and activity increased after DDC feeding and localized within and outside hepatocytes. KCC009 inhibited DDC-induced hepatomegaly by affecting hepatocyte cell size rather than proliferation. Hence, TG2 is a potential mediator of injury-induced hepatomegaly via modulation of hepatocyte hypertrophy, and KCC009-mediated TG2 inhibition does not affect mouse MB formation.

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Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas

Cited by 83 publications

References 33 publications

Reversal of Drug Resistance in Breast Cancer Cells by Transglutaminase 2 Inhibition and Nuclear Factor-κB Inactivation

Reversal of Drug Resistance in Breast Cancer Cells by Transglutaminase 2 Inhibition and Nuclear Factor-κB Inactivation

Tissue Transglutaminase Regulates Matrix Metalloproteinase-2 in Ovarian Cancer by Modulating cAMP-response Element-binding Protein Activity

Pharmacologic transglutaminase inhibition attenuates drug‐primed liver hypertrophy but not Mallory body formation

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