Tissue transglutaminase promotes or suppresses tumors depending on cell context

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 of high levels (>1 mM) of Ca(2+) induces its activation, which promotes inter- and intramolecular cross-linking of proteins and results in cell death. Indeed, the use of TG2-specific antisense RNA protects cells against stress-induced cell death. In contrast, low levels (<1 mM) of Ca(2+) and a high concentration (>9 microM) of guanosine triphosphate (the conditions that generally prevail inside cells) promotes TG2-mediated cell survival signaling. Many studies have reported increased TG2 expression in a number of cancer cell types that are known to have high resistance to chemotherapeutic drugs or are metastatic. Importantly, the increased expression of TG2 is associated with increased invasion and cell survival. Down-regulation of TG2 by small interfering RNA or inhibition by small molecule inhibitors can enhance therapeutic efficacy of anticancer drugs and inhibit metastatic spread. In this review, the contextual roles of TG2 in promoting and protecting normal versus tumor cells from death-induced signaling, its contributions in promoting the drug resistance and metastasis of cancer cells and its therapeutic potential for treating advanced cancer are discussed.