Abstract
Endocrine-disruptor chemicals (EDCs), such as bisphenol A (BPA) and nonylphenol (NP), have been widely studied due to their negative effects on human and wildlife reproduction. Exposure to BPA or NP is related to cell death, hormonal deregulation, and cancer onset. Our previous studies showed that both compounds induce A Disintegrin And Metalloprotease 17 (ADAM17) activation. Here, we show that BPA and NP induce apoptosis in prostate and ovary cancer cell lines, in a process dependent on ADAM17 activation. ADAM17 knockdown completely prevented apoptosis as well as the shedding of ADAM17 substrates. Both compounds were found to induce an increase in intracellular calcium (Ca2+) only in Ca2+-containing medium, with the NP-treated cells response being more robust than those treated with BPA. Additionally, using a phosphorylated protein microarray, we found that both compounds stimulate common intracellular pathways related to cell growth, differentiation, survival, and apoptosis. These results suggest that BPA and NP could induce apoptosis through ADAM17 by activating different intracellular signaling pathways that may converge in different cellular responses, one of which is apoptosis. These results confirm the capacity of these compounds to induce cell apoptosis in cancer cell lines and uncover ADAM17 as a key regulator of this process in response to EDCs.
Highlights
Endocrine-disruptor chemicals (EDCs) is the given name of a wide variety of compounds that disrupt the internal hormonal balance in humans and wildlife animals, leading to transient and/or permanent negative effects [1,2,3,4,5]
We have shown that Bisphenol A (BPA) and NP induce the release of Tumor Necrosis Factor α (TNF), Transforming Growth Factor α (TGFα), and Heparin-binding EGF-like Growth Factor (HB-EGF) from plasma membrane by A Disintegrin And Metalloprotease 17 (DAM17) [21,22,23], and that BPA and NP induce apoptosis in male germ cells by activating p38 MAPK and ADAM17 [23,24,25]
In this work we show that BPA and NP differentially induce apoptosis in cancer cell lines in a mechanism dependent upon ADAM17 and extracellular Ca2+, and we provide insights of possible mechanisms involved in the activation of ADAM17 by BPA and NP
Summary
Endocrine-disruptor chemicals (EDCs) is the given name of a wide variety of compounds that disrupt the internal hormonal balance in humans and wildlife animals, leading to transient and/or permanent negative effects [1,2,3,4,5]. BPA treatment upregulates matrix metalloproteases and apoptosis-related genes in the ovarian cancer cell line SKOV3 [20] This information only adds to the wide range of negative effects of these compounds. Other studies have shown that in vitro NP induces the apoptosis of neurons and thymocytes [28,29] in a mechanism that depends on the increased intracellular calcium (Ca2+) concentration ([Ca2+]i) induced by NP [30] Both compounds have been shown to modulate in vitro intracellular Ca2+ levels in different cell types [31,32,33,34,35], suggesting that it is possible to hypothesize a mechanistic relationship between perturbed Ca2+ levels, ADAM17 activation, and cell apoptosis. In this work we show that BPA and NP differentially induce apoptosis in cancer cell lines in a mechanism dependent upon ADAM17 and extracellular Ca2+, and we provide insights of possible mechanisms involved in the activation of ADAM17 by BPA and NP
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