Augmentation of Tissue Transglutaminase Expression and Activation by Epidermal Growth Factor Inhibit Doxorubicin-induced Apoptosis in Human Breast Cancer Cells

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

“…Increased expression of transglutaminase 2 (TGase 2; EC 2.3.2.13) is associated with drug resistance in breast cancer (1)(2)(3). Although the mechanism is as yet undefined, it seems that TGase 2 inhibition may completely reverse the drug-resistant phenotype of certain breast cancer cell lines (3).…”

“…Although the mechanism is as yet undefined, it seems that TGase 2 inhibition may completely reverse the drug-resistant phenotype of certain breast cancer cell lines (3). TGase 2 is a calcium-dependent enzyme that catalyzes the formation of covalent bonds between free amine groups in one protein and protein-bound glutamines of another, creating highly cross-linked protein complexes (4).…”

“…TGase 2 is ubiquitously expressed and has multiple normal physiologic functions through the targeting of specific substrates, such as blood clotting (5), wound healing (6), cell adhesion (7), apoptosis (8), and barrier formation (9). TGase 2 has also been associated with certain pathologic conditions [i.e., inflammatory diseases, such as encephalomyelitis (10), inflammatory myopathies (11), and celiac disease (12), as well as various types of cancer (1)(2)(3)(13)(14)(15)(16)(17)]. Long-term studies of patients with celiac disease have led to a model for disease progression, in which antigen modification by TGase 2 creates a novel epitope, which then can trigger an immune reaction in genetically predisposed individuals (18).…”

“…This was also true of invasive and metastatic breast cancer cells (2). Antonyak et al showed that TGase 2 inhibition using a dominantnegative form of TGase 2 abolished epidermal growth factor (EGF)-mediated protection from doxorubicin-induced apoptosis in several breast cancer cell lines (3). TGase 2 may protect cells from apoptosis by interacting with the retinoblastoma protein (19) or by promoting interactions between cell surface integrins (20).…”

“…It has also been shown that inhibition of NF-nB enhances the sensitivity of tumor cells to apoptosis induced by chemotherapeutic agents (26). TGase 2 expression can be induced by EGF (3,27). Therefore, in the current study, we examined several different breast cancer cell lines, representing EGF receptor (EGFR)-positive and EGFR-negative breast cancers, to determine the role of TGase 2-mediated NF-nB activation in drug resistance.…”