Tissue transglutaminase-mediated chemoresistance in cancer cells

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 beta members of the integrin family of proteins (beta1, beta3, beta4, and beta5) 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 IkappaB/p65:p50 and results in constitutive activation of the nuclear transcription factor-kappaB (NF-kappaB). 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.