Abstract
Nrf2 and TGF-β1 both affect tumorigenesis in a dual fashion, either by preventing carcinogen induced carcinogenesis and suppressing tumor growth, respectively, or by conferring cytoprotection and invasiveness to tumor cells during malignant transformation. Given the involvement of Nrf2 and TGF-β1 in the adaptation of epithelial cells to persistent inflammatory stress, e.g. of the pancreatic duct epithelium during chronic pancreatitis, a crosstalk between Nrf2 and TGF-β1 can be envisaged. By using premalignant human pancreatic duct cells (HPDE) and the pancreatic ductal adenocarcinoma cell line Colo357, we could show that Nrf2 and TGF-β1 independently but additively conferred an invasive phenotype to HPDE cells, whereas acting synergistically in Colo357 cells. This was accompanied by differential regulation of EMT markers like vimentin, Slug, L1CAM and E-cadherin. Nrf2 activation suppressed E-cadherin expression through an as yet unidentified ARE related site in the E-cadherin promoter, attenuated TGF-β1 induced Smad2/3-activity and enhanced JNK-signaling. In Colo357 cells, TGF-β1 itself was capable of inducing Nrf2 whereas in HPDE cells TGF-β1 per-se did not affect Nrf2 activity, but enhanced Nrf2 induction by tBHQ. In Colo357, but not in HPDE cells, the effects of TGF-β1 on invasion were sensitive to Nrf2 knock-down. In both cell lines, E-cadherin re-expression inhibited the proinvasive effect of Nrf2. Thus, the increased invasion of both cell lines relates to the Nrf2-dependent downregulation of E-cadherin expression. In line, immunohistochemistry analysis of human pancreatic intraepithelial neoplasias in pancreatic tissues from chronic pancreatitis patients revealed strong Nrf2 activity already in premalignant epithelial duct cells, accompanied by partial loss of E-cadherin expression. Our findings indicate that Nrf2 and TGF-β1 both contribute to malignant transformation through distinct EMT related mechanisms accounting for an invasive phenotype. Provided a crosstalk between both pathways, Nrf2 and TGF-β1 mutually promote their tumorigenic potential, a condition manifesting already at an early stage during inflammation induced carcinogenesis of the pancreas.
Highlights
The antioxidant transcription factor Nuclear factor E2 related factor-2 (Nrf2) and the cytokine Transforming growth factor beta1 (TGF-β1) both have a dual role in carcinogenesis [1,2,3,4,5,6,7,8]
To investigate the status of Nrf2 activation and its crosstalk with TGF-β1, the nuclear protein level of Nrf2 was analysed in the nontumorigenic pancreatic ductal epithelial cell line human pancreatic duct cells (HPDE) exhibiting low Nrf2 activity [33] by westernblot
an inhibitory Nrf2 binding site (ARE)-luciferase assays (Fig 1B) revealed an increase of Nrf2 activity in HPDE cells when treated with tBHQ or SFN but not with TGF-β1, and an even stronger Nrf2 activity after combined treatment
Summary
The antioxidant transcription factor Nuclear factor E2 related factor-2 (Nrf2) and the cytokine Transforming growth factor beta (TGF-β1) both have a dual role in carcinogenesis [1,2,3,4,5,6,7,8]. By inducing a battery of cytoprotective and detoxifying or antioxidant enzymes, Nrf mitigates stress induced damage of cell components like DNA and prevents mutagenesis. Based on these effects, Nrf was regarded as being anti-tumorigenic and to serve as beneficial target in chemoprevention [10,11,12]. The growth advantages of cancer cells depending on Nrf include apoptosis protection and chemo-/radioresistance [18,19,20], increased proliferation rates [21,22], greater invasiveness [23,24] and angiogenesis [25,26], and an altered metabolism [27,28]
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