Cancer is a leading cause of death worldwide accounting for 8.2 million deaths each year. As a result of genetic alterations, cancer cells accumulate defects in regulatory circuits that govern normal cell proliferation and homeostasis. Cancer cells may acquire the capability to sustain proliferation, resist cell death, evade growth suppression, enable replicative immortality, induce angiogenesis, and activate invasion/metastasis. Apoptotic pathways are frequently dysfunctional in cancer cells, and breaking the resistance of tumors to cell death is one of the major anti-cancer approaches.
Protein disulfide isomerases (Pdis), a family of multifunctional enzymes, are thought to regulate human health and disease. Pdia4 is the biggest Pdi member with three CGHC motifs. Of note, Pdia4 is barely expressed in normal tissues. However, its expression is further up-regulated in various cancer cells. Importantly, Pdia4 promotes cancer development and metastasis. Knockdown and overexpression of Pdia4 in tumor cells showed that Pdia4 facilitated cell growth via the reduction of caspase 3 and 7 activity. Consistently, Pdia4 promotes cancer development in mice models of cancer as shown by a reduced survival rate, increased tumor size and metastasis, and decreased cell death and caspase 3 and 7 activity. Pdia4 knockdown resulted in opposite outcomes. Mechanistic studies illustrated that Pdia4 negatively regulated cancer cell death by inhibiting degradation and activation of procaspases 3 and 7 via their mutual interaction in a CGHC-dependent manner. As a result, Pdia4 inhibitors reduced cancer development via enhancement of caspase-mediated cell death in tumor-bearing mice. The findings characterize Pdia4 as a negative regulator of cancer cell apoptosis and suggest that Pdia4 is a potential therapeutic target for cancer.
The laboratory of Dr Yang Wen-Chin, Agricultural Biotechnology Research Center of Academia Sinica, has aimed at cancer research and drug development for 17 years. This invention is to use Pdia4 to diagnose and treat patients with a variety of cancers. Pdia4 inhibitor can be chemically synthesized as anti-cancer lead. This inhibitor can inhibit the enzymatic activity of Pdia4 and promote cancer cell apoptosis, leading to cancer development and metastasis in mice with cancers.