Millions of people around the world regularly drink arsenic-contaminated water. Exposure to arsenic has already been linked to the development of various cancers, including skin cancer. Research on the underlying molecular mechanisms regulating arsenic-mediated carcinogenesis remains scarce. Using in vitro studies, Japanese researchers demonstrate how calcitriol, or activated vitamin D3, inhibits arsenic-mediated carcinogenesis in certain types of skin cells called “keratinocytes”.
According to recent estimates, more than 140 million people in 50 countries are regularly exposed to arsenic through drinking water. The level of exposure greatly exceeds the guideline value (10 μg/L) stipulated by the World Health Organization. It is an established fact that chronic exposure to arsenic from drinking water causes a variety of cancers, including skin cancer. Unfortunately, there is a general lack of data on the underlying biological mechanisms that regulate arsenic-mediated carcinogenesis. Moreover, methods for the prevention and treatment of arsenic-mediated carcinogenesis have remained elusive until now.
Researchers from the Shibaura Institute of Technology (SIT) and the University of Nagoya have recently been able to identify the biological mechanisms underlying the inhibition of carcinogenesis. Using in vitro studies, the research team was able to demonstrate how calcitriol, or activated vitamin D3, inhibits arsenic-mediated carcinogenesis in certain types of skin cells called “keratinocytes”. These cells are mainly found in the epidermis, the outermost layer of the skin. It is a scientifically established fact that certain signaling molecules – protein kinases (eg, MEK or “AKT”) that control the fate of various biological processes – are strongly associated with tumor development.
Professor Ichiro Yajima of the Molecular and Cellular Toxicology Unit of the Department of Biosciences and Engineering at SIT, who led the research team, says: “Our in vitro study on non-tumorigenic human HaCaT skin keratinocytes has showed that calcitriol, also known as activated vitamin D3 or 1,25-dihydroxy-vitamin D3, inhibited arsenic-mediated anchorage-independent growth with downregulations of activation linked to cancer of several signaling pathways, including MEK, ERK1/2 and AKT, as well as cell cycle activity.
To elucidate the relationship between arsenic uptake and calcitriol treatment, the researchers measured arsenic levels in HaCaT cells – long-lived, spontaneously immortalized human epidermal keratinocytes – treated with calcitriol at using an inductively coupled plasma mass spectrophotometer. Interestingly enough, arsenic levels in HaCaT cells cultured with arsenic decreased significantly when these cells were treated with increasing doses of calcitriol. The results of their study were published in the American Journal of Cancer Research.
Dr. Masashi Kato, a professor in the Department of Occupational and Environmental Health at Nagoya University, Japan, and study collaborator, adds: “Calcitriol significantly suppressed arsenic uptake in HaCaT cells with regulating expressions of the aquaporin genes (AQP7, 9 and 10), which were altered by exposure to arsenic. Vitamin D receptor expression was significantly increased by arsenic exposure, whereas calcitriol had no effect on receptor expression.
The researchers then sought to understand whether calcitriol had an inhibitory effect on arsenic-induced tumorigenesis in cells other than skin keratinocytes. To this end, they performed anchorage-independent growth assays using a normal human lung epithelial cell line called “Beas-2b”. The results of these assays were equally astonishing: arsenic-induced anchorage-independent growth of Beas-2b cells treated with calcitriol was suppressed by 21.4-70.0%, suggesting that the potential of calcitriol to suppress arsenic-induced tumorigenesis is not limited to keratinocytes.
Professor Yajima reflects: “These results suggest that calcitriol suppresses arsenic-induced tumorigenesis not only in keratinocytes, but also in other target cells, including lung epithelial cells. Moreover, the expression pattern of aquaporin genes involved in arsenic uptake, a critical step in induced carcinogenesis, is significantly altered by calcitriol treatment. We therefore believe that activated vitamin D3, or calcitriol, may aid in the prevention and treatment of arsenic-mediated diseases, including cancer.
Environmental toxins such as arsenic contribute significantly to the development of life-threatening diseases such as cancer. However, it can take years or even decades for cancer to develop from drinking arsenic-contaminated water. Current research clearly indicates that calcitriol might be used as a test compound to validate the safety and efficacy of activated vitamin D3 and/or its analogs in the prevention or treatment of arsenic-triggered cancer. Taking vitamin D3 beforehand in areas contaminated with arsenic can reduce the risk of developing cancer 5 or 10 years later and help people stay healthy for a long time. This is certainly good news for millions of people forced to survive with polluted water around the world.
