Prostate Cancer Malignancy Is Enhanced by Glycotoxins(3/3)

Advanced glycation end products (AGEs), also known as glycotoxins, are a diverse group of highly reactive compounds with pathogenic significance in diabetes and in several other chronic diseases. AGEs are created through a nonenzymatic reaction between reducing sugars and free amino groups of proteins, lipids, or nucleic acids. The formation of AGEs is a part of normal metabolism, but if excessively high levels of AGEs are reached in tissues and the circulation they could become pathogenic. The pathologic effects of AGEs are related to their ability to promote oxidative stress and inflammation by binding with the receptor for AGEs (RAGE) or crosslinking with body proteins, altering their structure and function. In addition to AGEs that form within the body, AGEs also exist in foods. Modern diets are largely heat-processed and as a result contain high levels of AGEs. Because it had previously been assumed that dietary AGEs are poorly absorbed, their potential role in human health and disease was largely ignored. However, the findings from animal and human studies suggest that avoidance of AGEs exposure helps delay cancer malignancy in animals and possibly in human beings. Dietary factors are important for the development of prostate cancer and AGEs formation, and RAGE has aggressive roles related to metastasis and invasion in some cancers. Nevertheless, the involvement of AGEs-RAGE interaction in prostate cancer’s drug resistance has not been fully elucidated. According to our preliminary data, chemotherapy resistance of DU 145 and PC-3 prostate cancer cells is enhanced by AGEs treatment. Targeted knockdown of RAGE in the tumor cells, leads to increased apoptosis, diminished autophagy and decreased tumor cell survival. In contrast, overexpression of RAGE is associated with enhanced autophagy, diminished apoptosis and greater tumor cell viability. Thus, the goals of this project are to (1) investigate the role of AGEs in the chemoresistance of prostate cancer. (2) Generation of RAGE-overexpression and -knockdown stable prostate cancer cell lines to dissect the crosstalk between AGEs and RAGE signaling in response to chemodrug injury, and (3) in vivo verify whether expression levels of RAGE affected sensitivity to chemotherapy by tumor xenograft model. With further investigation, our study might provide insight into the development of novel clinical therapies targeting AGEs-RAGE pathway.