Connections between endoplasmic reticulum stress-associated unfolded protein response, mitochondria, and autophagy in arsenic-induced carcinogenesis.

Arsenic exposure in contaminated drinking water is a global health issue, as more than 200 million people are affected globally. Arsenic has been known to cause skin, liver, lung, bladder and prostate cancers. Accordingly, it has been categorized as a group I human carcinogen by the International Agency for Research on Cancer (IARC). Various natural and anthropogenic activities lead to the release of arsenic in the environment, contaminating air, water and food sources. Traditionally, genetic mutations have been the center of cancer research. However, emerging studies have now focused on the importance of epigenetics, metabolism and endoplasmic reticulum (ER) stress in cancer. Arsenic is highly capable of inducing stress in the cells via the generation of free radicals causing oxidative stress, epigenetic and genetic alterations, mitochondrial dysfunction, activation of intracellular signaling pathways, and impairment of autophagy and DNA repair systems. The cancer cells are able to utilize the unfolded protein response (UPR) to overcome these internal stresses in various stages of arsenic-induced carcinogenesis, from cancer growth to immune responses. The UPR is an evolutionarily conserved stress response that has both survival and apoptotic outcomes. PERK, IRE1α and ATF6α are the three ER stress sensors that are activated to maintain cellular proteostasis, which can also promote apoptosis on prolonged ER stress. The dual nature of UPR in different cancer types and stages is a challenge for researchers. We must investigate the role and the connections among ER stress-associated UPR, mitochondrial dysfunction and autophagy in arsenic malignancies to identify key targets for cancer prevention and therapeutics.