Targeting transglutaminase-2 to overcome chemoresistance in cancer cells

The ability of tumor cells to develop resistance to chemotherapy and radiation therapy and to metastasize to distant organs represents a major roadblock in the successful treatment of cancer. In fact, more than 90% of cancer deaths can be attributed to the failure of drugs to kill tumor cells. One feature common among drug-resistant and metastatic tumor cells is an increased resistance to apoptosis-the ability of cancer cells not only to grow and survive successfully in the stressful environments of foreign tissues (metastasis) but also to display resistance to genotoxic therapies. Therefore, to improve cancer therapy, tumor-encoded genes, whose increased expression in cancer cells contributes to the development of resistance to drug-induced damage (apoptosis), need to be defined. One such gene is TGM2 (NM-004613), whose expression is upregulated in many drug-resistant and metastatic tumors and tumor cell lines. The product of the TGM2 gene, tissue type transglutaminase-2(TG2), is structurally and functionally a complex protein that is implicated in such diverse processes as apoptosis, wound healing, cell migration, cell attachment, cell growth, angiogenesis, and matrix assembly. In this chapter, we will provide recent evidence linking aberrant expression of TG2 with the development of chemoresistance and a metastatic phenotype in cancer cells. In addition, we will discuss some specific antiapoptotic pathways that are regulated by TG2 and how inhibition or downregulation of this protein can enhance the sensitivity of cancer cells to conventional chemotherapy.