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Published on: January 12, 2020
Constitutively active Notch1 induces growth arrest of HPV-positive cervical cancer cells via separate signaling
Claudio Talora1, Samantha Cialfi, Oreste Segatto
1Department of Experimental Medicine and Pathology, Laboratory of Molecular Pathology, University La Sapienza, Viale Regina Elena, 324, 00161 Rome, Italy.
Abstract:
Notch signaling plays a key role in cell-fate determination and differentiation in different organisms and cell types. Several reports suggest that Notch signaling may be involved in neoplastic transformation. However, in primary keratinocytes, Notch1 can function as a tumor suppressor. Similarly, in HPV-positive cervical cancer cells, constitutively active Notch1 signaling was found to cause growth suppression. Activated Notch1 in these cells represses viral E6/E7 expression through AP-1 down-modulation, resulting in increased p53 expression and a block of pRb hyperphosphorylation. Here we show that in cervical cancer cell lines in which Notch1 ability to repress AP-1 activity is impaired, Notch1-enforced expression elicits an alternative pathway leading to growth arrest. Indeed, activated Notch1 signaling suppresses activity of the helix-loop-helix transcription factor E47, via ERK1/2 activation, resulting in inhibition of cell cycle progression. Moreover, we found that RBP-Jkappa-dependent Notch signaling is specifically repressed in cervical cancer cells and this repression could provide one such mechanism that needs to be activated for cervical carcinogenesis. Finally, we show that inhibition of endogenous Notch1 signaling, although results in a proliferative advantage, sensitizes cervical cancer cell lines to drug-induced apoptosis. Together, our results provide novel molecular insights into Notch1-dependent growth inhibitory effects, counteracting the transforming potential of HPV.
Insights
Notch1 signaling acts as a tumor suppressor in cervical cancer by inhibiting viral gene expression and cell cycle progression. Its repression is crucial for cervical cancer development, and its inhibition sensitizes cells to chemotherapy.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Notch signaling is crucial for cell differentiation and implicated in cancer.
- Notch1 can act as a tumor suppressor, notably in HPV-positive cervical cancer cells.
- Activated Notch1 signaling suppresses growth in cervical cancer by repressing viral E6/E7 expression.
Purpose of the Study:
- To investigate the molecular mechanisms of Notch1's tumor-suppressive role in cervical cancer.
- To elucidate alternative pathways of Notch1-mediated growth arrest when AP-1 repression is impaired.
- To determine the role of RBP-Jkappa-dependent Notch signaling in cervical carcinogenesis.
Main Methods:
- Utilized cervical cancer cell lines with varying Notch1 pathway activity.
- Analyzed the impact of activated Notch1 on viral gene expression (E6/E7), AP-1, p53, and pRb.
- Investigated Notch1's interaction with E47 transcription factor and ERK1/2 signaling.
- Assessed the role of RBP-Jkappa-dependent signaling and the effect of Notch1 inhibition on drug sensitivity.
Main Results:
- Activated Notch1 signaling induces growth arrest via E47 suppression and ERK1/2 activation when AP-1 repression is impaired.
- RBP-Jkappa-dependent Notch signaling is specifically repressed in cervical cancer cells.
- Inhibition of endogenous Notch1 signaling promotes proliferation but sensitizes cells to apoptosis.
- Notch1 signaling counteracts HPV-driven transformation through distinct molecular pathways.
Conclusions:
- Notch1 exerts growth inhibitory effects in cervical cancer through multiple mechanisms, including E47 suppression and modulation of viral oncogenes.
- Repression of Notch1 signaling is a key event in cervical carcinogenesis.
- Targeting Notch1 signaling may offer therapeutic strategies for cervical cancer, enhancing drug efficacy.
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