Arsenite-Mediated Promotion of Anchorage-Independent Growth of HaCaT Cells through Placental Growth Factor

Abstract

Various cancers including skin cancer are increasing in 45 million people exposed to arsenic above the World Health Organization's guideline value of 10 μg l(-1). However, there is limited information on key molecules regulating arsenic-mediated carcinogenesis. Our fieldwork in Bangladesh demonstrated that levels of placental growth factor (PlGF) in urine samples from residents of cancer-prone areas with arsenic-polluted drinking water were higher than those in urine samples from residents of an area that was not polluted with arsenic. Our experimental study in human nontumorigenic HaCaT skin keratinocytes showed that arsenite promoted anchorage-independent growth with increased expression and secretion of PlGF, a ligand of vascular endothelial growth factor receptor1 (VEGFR1), and increased VEGFR1/mitogen-activated protein kinase/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) activities. The arsenite-mediated promotion of anchorage-independent growth was strongly inhibited by PlGF depletion with decreased activities of the PlGF/VEGFR1/MEK/ERK pathway. Moreover, arsenite proteasome-dependently degrades metal-regulatory transcription factor-1 (MTF-1) protein, resulting in a decreased amount of MTF-1 protein binding to the PlGF promoter. MTF-1 negatively controlled PlGF transcription in HaCaT cells, resulting in increased PlGF transcription. These results suggest that arsenite-mediated MTF-1 degradation enhances the activity of PlGF/VEGFR1/MEK/ERK signaling, resulting in promotion of the malignant transformation of keratinocytes. Thus, this study proposed a molecular mechanism for arsenite-mediated development of skin cancer.

Multidisciplinary approach to assess the toxicities of arsenic and barium in drinking water

“…We therefore performed a fieldwork study focusing on urinary PlGF levels in Bangladeshi residents of cancer-prone areas. As expected, the urinary PlGF levels in residents of cancerprone areas with high levels of arsenic in well drinking water were significantly higher than those in residents of a control area with limited pollution of arsenic in well drinking water [1].…”

“…Thus, PlGF might play a role in arsenic-mediated skin cancer development (Fig. 2) [1]. We therefore performed a fieldwork study focusing on urinary PlGF levels in Bangladeshi residents of cancer-prone areas.…”

“…Since there are less pathogenic microbes in well water than in lake or pond water, the use of well water as drinking water has been accelerating in developing countries. Unfortunately, however, many kinds of disorders caused by toxic elements in well drinking water (element-originating diseases) have been reported in developing countries [1][2][3][4][5]. It is our urgent task to resolve the global issues that are directly associated with human life.…”

Chronic arsenic trioxide exposure leads to enhanced aggressiveness via Met oncogene addiction in cancer cells

“…Arsenicosis, as the most common phenotype of exposed people, is also the best example of arsenic-induced cell transformation. Many studies have addressed this issue and suggested different molecular mechanisms [ 25 , 26 ]. Interestingly, although tumorigenic capability of chronic arsenic exposure as a single agent was not conclusively confirmed in animal models, there is strong evidence for the co-carcinogenic potential if combined with other carcinogens like UV light, N-methyl-N-nitrosourea, diepoxybutane, X-rays, methylmethane sulfonate, and tobacco [ 5 , 11 , 27 ].…”

Intranasal levels of lead as an exacerbation factor for allergic rhinitis in humans and mice

“…In accordance with previous studies, 31,32 urinary levels of Pb, Cd, and Hg were presented as the concentrations equal to 1 g of creatinine according to the following formula:…”