Tissue transglutaminase: a new target to reverse cancer drug resistance (original) (raw)
Related papers
Tissue transglutaminase promotes or suppresses tumors depending on cell context
Anticancer research, 2009
Despite major advances in diagnosis, surgical and postsurgical techniques and adjuvant therapies, 7.5 million individuals worldwide still die of cancer every year. Most cancer deaths result because tumor cells metastasize to distant organs and/or acquire resistance to conventional therapies. Therefore, elucidation of tumor-encoded genes whose expression contribute to the development of drug resistance and metastasis can be of great significance in revealing novel therapeutic targets for the effective control and treatment of cancer. Tissue transglutaminase (TG2) is an enzyme whose expression is up-regulated in a number of cancer cell types. TG2 is a ubiquitous member of the transglutaminase family of enzymes and is implicated in such diverse processes as inflammation, wound healing, apoptosis, neurodegenerative disorders and cancer. Depending on the cell type and its localization within the cell, TG2 can serve as an antiapoptotic or a proapoptotic protein. In general, the presence o...
Tissue transglutaminase-mediated chemoresistance in cancer cells
Drug Resistance Updates, 2007
Drug resistance and metastasis are major impediments for the successful treatment of cancer. A common feature among drug resistant and metastatic tumor cells is that they exhibit profound resistance to apoptosis. This property enables cancer cells not only to grow and survive in stressful environments (metastasis) but also to display resistance against many anticancer agents. Therefore, perturbation of the intrinsic apoptotic pathways of cancer cells will affect their ability to respond to chemotherapy and to metastasize and survive in distant sites. Recent studies have demonstrated that cancer cells and cancer cell lines selected for resistance against chemotherapeutic drugs or isolated from metastatic sites, express elevated levels of the multifunctional protein, tissue transglutaminase (TG2). TG2 is the most diverse and ubiquitous member of the transglutaminase family of proteins that is implicated to play a role in apoptosis, wound healing, cell migration, cell attachment, cell growth, angiogenesis, and matrix assembly. TG2 can associate with certain  members of the integrin family of proteins (1, 3, 4, and 5) and promote stable interaction between cells and the extracellular matrix (ECM), resulting in increased cell survival, cell migration, and invasion. Additionally, TG2 forms a ternary complex with IB/p65:p50 and results in constitutive activation of the nuclear transcription factor-B (NF-B). Moreover, TG2 expression in cancer cells leads to constitutive activation of the focal adhesion kinase (FAK) and its downstream PI3K/Akt survival pathway. Importantly, the inhibition of endogenous TG2 by small interfering RNA (siRNA) resulted in the reversal of drug resistance and the invasive phenotype. Conversely, ectopic expression of TG2 promoted cell survival, cell motility and invasive functions of cancer cells. This review discusses the current thinking and implications of increased TG2 expression in development of drug resistance and metastasis by cancer cells.
Oncogene, 2006
The development of resistance to chemotherapeutic drugs is a major obstacle to the successful treatment of breast cancer. Ways to block or overcome this resistance are objects of intense research. We have previously shown that cancer cells selected for resistance against chemotherapeutic drugs or isolated from metastatic tumor sites have high levels of a calcium-dependent protein crosslinking enzyme, tissue transglutaminase (TG2) but no direct link between TG2 and resistance was established. As TG2 can associate with the b members of the integrin family of proteins, we hypothesized that TG2 promotes cell survival signaling pathways by activating integrins on the surface of these cells. To test this hypothesis, we studied the expression of TG2 and its interaction with various integrins in drug-resistant MCF-7 breast cancer cells. TG2 closely associated with b1 and b5 integrins on the surface of drug-resistant MCF-7 (MCF-7/Dox and MCF-7/RT) cells. The incubation of TG2-expressing drug-resistant MCF-7 cells on fibronectin (Fn)-coated surfaces strongly activated focal adhesion kinase, an event that leads to the activation of several downstream signaling pathways and, in turn, can confer apoptosisresistant phenotype to cancer cells. The role of TG2 in Fnmediated cell attachment, cell growth, and cell survival functions was further analysed by small interfering RNA (siRNA) approach. Inhibition of TG2 by siRNA-inhibited Fn-mediated cell attachment and cell survival functions in drug-resistant MCF-7 cells. We conclude that the expression of TG2 in breast cancer cells contributes to the development of the drug-resistance phenotype by promoting interaction between integrins and Fn.
Tissue transglutaminase: from biological glue to cell survival cues
2006
Introduction 3. Tissue transglutaminase as the enzyme with a split personality 3.1. TG2 as pro-and anti-apoptotic protein 3.2. TG2, drug resistance and metastasis 3.3. TG2 and integrin connection 3.4. TG2 as host's response to tumor 3.5. TG2 and carcinogenesis 4. Summary and Prospective 5. Acknowledgement 6. References p53 Mutated/altered expression in many cancers. p53-deficient cells are resistant to drug-induced apoptosis Bcl-2 Overexpressed in many tumors. Inhibits drug-induced apoptosis Bax Mutated or decreased expression in many tumors. Sufficient but not necessary for drug-induced apoptosis Bak Mutated or decreased expression in many tumors. Sufficient but not necessary for drug-induced apoptosis Apaf-1 Mutated or silenced in melanoma and leukemia cell lines. Apaf-1-deficient cells are chemoresistant CD-95/Fas mutated/down regulated in lymphoid and solid tumors. Loss is associated with resistance to drug-induced apoptosis TRAIL-R1/R2 Mutated in metastatic breast cancer. Mutation leads to suppression of death receptor-mediated apoptosis Caspase-8 Gene silenced in neuroblastoma, which results in drug-induced apoptosis IAPs Over expressed in cancer. Down-regulation results in apoptosis in chemoresistant tumors NF-κB Constitutively activated in many tumors. Can induce resistance to drug-induced apoptosis Akt Often amplified in solid tumors. Induces resistance to a variety of apoptosis-inducing stimuli, including drugs PTEN Mutated or altered expression in many cancer. Regulates Akt activation. Loss of PTEN results in resistance to apoptosis PI3K Expression altered in some cancers. Inhibition enhances drug-induced apoptosis Ras Mutated and activated in many cancers. Inhibits drug-induced apoptosis FLIP Overexpressed in some cancers. Prevents apoptosis induced by some chemotherapeutic drugs
Prognostic Significance of Tissue Transglutaminase in Drug Resistant and Metastatic Breast Cancer
Clinical Cancer Research, 2004
Purpose: Drug resistance and metastasis pose major impediments in the successful treatment of cancer. We previously reported that multidrug-resistant breast cancer cells exhibit high levels of tissue transglutaminase (TG2; EC 2.3.2.13). Because the drug-resistant and metastatic phenotypes are thought to share some common pathways, we sought to determine whether metastatic breast cancer cells express high levels of TG2. Experimental Design: The metastatic breast cancer cell line MDA-MB-231 and the sublines derived from it were tested for TG2 expression. Similarly, several sublines derived from an immortal but normal breast epithelial cell line, MCF10A, representing various stages in breast cancer progression were studied for TG2 expression. The primary and nodal tumor samples from 30 patients with breast cancer were also studied for TG2 expression. Results: The MDA-MB-231 cells expressed high basal levels of TG2. Two clones derived from this cell line, MDA231/cl.9 and MDA231/cl.16, showed a 10-to 15-fold difference in TG2 level. TG2-deficient MDA231/cl.9 cells exhibited higher sensitivity to doxorubicin and were less invasive than were the TG2-sufficient MDA231/cl.16 cells. The MCF10A-derived sublines had increased TG2 expression as they advanced from noninvasive to an invasive phenotype. Importantly, the metastatic lymph node tumors from patients with breast cancer showed significant higher levels of TG2 expression compared with the primary tumors from the same patients. Conclusions: TG2 expression is up-regulated in drugresistant and metastatic breast cancer cells, and it can serve as a valuable prognostic marker for these phenotypes.
The Role of Tissue Transglutaminase in Cancer Cell Initiation, Survival and Progression
Medical Sciences
Tissue transglutaminase (transglutaminase type 2; TG2) is the most ubiquitously expressed member of the transglutaminase family (EC 2.3.2.13) that catalyzes specific post-translational modifications of proteins through a calcium-dependent acyl-transfer reaction (transamidation). In addition, this enzyme displays multiple additional enzymatic activities, such as guanine nucleotide binding and hydrolysis, protein kinase, disulfide isomerase activities, and is involved in cell adhesion. Transglutaminase 2 has been reported as one of key enzymes that is involved in all stages of carcinogenesis; the molecular mechanisms of action and physiopathological effects depend on its expression or activities, cellular localization, and specific cancer model. Since it has been reported as both a potential tumor suppressor and a tumor-promoting factor, the role of this enzyme in cancer is still controversial. Indeed, TG2 overexpression has been frequently associated with cancer stem cells’ survival,...
The Outside-In Journey of Tissue Transglutaminase in Cancer
Cells
Tissue transglutaminase (TG2) is a member of the transglutaminase family that catalyzes Ca2+-dependent protein crosslinks and hydrolyzes guanosine 5′-triphosphate (GTP). The conformation and functions of TG2 are regulated by Ca2+ and GTP levels; the TG2 enzymatically active open conformation is modulated by high Ca2+ concentrations, while high intracellular GTP promotes the closed conformation, with inhibition of the TG-ase activity. TG2’s unique characteristics and its ubiquitous distribution in the intracellular compartment, coupled with its secretion in the extracellular matrix, contribute to modulate the functions of the protein. Its aberrant expression has been observed in several cancer types where it was linked to metastatic progression, resistance to chemotherapy, stemness, and worse clinical outcomes. The N-terminal domain of TG2 binds to the 42 kDa gelatin-binding domain of fibronectin with high affinity, facilitating the formation of a complex with β-integrins, essential ...
Matrix changes induced by transglutaminase 2 lead to inhibition of angiogenesis and tumor growth
Cell Death and Differentiation, 2006
Administration of active TG2 to two different in vitro angiogenesis assays resulted in the accumulation of a complex extracellular matrix (ECM) leading to the suppression of endothelial tube formation without causing cell death. Matrix accumulation was accompanied by a decreased rate of ECM turnover, with increased resistance to matrix metalloproteinase-1. Intratumor injection of TG2 into mice bearing CT26 colon carcinoma tumors demonstrated a reduction in tumor growth, and in some cases tumor regression. In TG2 knockout mice, tumor progression was increased and survival rate reduced compared to wild-type mice. In wild-type mice, an increased presence of TG2 was detectable in the host tissue around the tumor. Analysis of CT26 tumors injected with TG2 revealed fibrotic-like tissue containing increased collagen, TG2-mediated crosslink and reduced organized vasculature. TG2-mediated modulation of cell behavior via changes in the ECM may provide a new approach to solid tumor therapy.
International Journal of Molecular Sciences
Transglutaminase 2 (TG2) is a multifunctional enzyme primarily responsible for crosslinking proteins. Ubiquitously expressed in humans, TG2 can act either as a transamidase by crosslinking two substrates through formation of an Nε(ɣ-glutaminyl)lysine bond or as an intracellular G-protein. These discrete roles are tightly regulated by both allosteric and environmental stimuli and are associated with dramatic changes in the conformation of the enzyme. The pleiotropic nature of TG2 and multi-faceted activities have resulted in TG2 being implicated in numerous disease pathologies including celiac disease, fibrosis, and cancer. Targeted TG2 therapies have not been selective for subcellular localization, such that currently no tools exist to selectively target extracellular over intracellular TG2. Herein, we have designed novel TG2-selective inhibitors that are not only highly potent and irreversible, but also cell impermeable, targeting only extracellular TG2. We have also further deriva...
PLoS ONE, 2010
Recent observations that aberrant expression of tissue transglutaminase (TG2) promotes growth, survival, and metastasis of multiple tumor types is of great significance and could yield novel therapeutic targets for improved patient outcomes. To accomplish this, a clear understanding of how TG2 contributes to these phenotypes is essential. Using mammary epithelial cell lines (MCF10A, MCF12A, MCF7 and MCF7/RT) as a model system, we determined the impact of TG2 expression on cell growth, cell survival, invasion, and differentiation. Our results show that TG2 expression promotes drug resistance and invasive functions by inducing epithelial-mesenchymal transition (EMT). Thus, TG2 expression supported anchorageindependent growth of mammary epithelial cells in soft-agar, disrupted the apical-basal polarity, and resulted in disorganized acini structures when grown in 3D-culture. At molecular level, TG2 expression resulted in loss of E-cadherin and increased the expression of various transcriptional repressors (Snail1, Zeb1, Zeb2 and Twist1). Tumor growth factor-beta (TGF-b) failed to induce EMT in cells lacking TG2 expression, suggesting that TG2 is a downstream effector of TGF-b-induced EMT. Moreover, TG2 expression induced stem cell-like phenotype in mammary epithelial cells as revealed by enrichment of CD44 + /CD24-/low cell populations. Overall, our studies show that aberrant expression of TG2 is sufficient for inducing EMT in epithelial cells and establish a strong link between TG2 expression and progression of metastatic breast disease.