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Published on: January 12, 2020
Notch1 signaling modulates hypoxia-induced multidrug resistance in human laryngeal cancer cells
Dawei Li1, Dan Xu2, Penghui Chen1
1Department of Otorhinolaryngology Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 200092, Shanghai, China.
Background:
Laryngeal carcinoma is one of the common malignant tumors of the head and neck. Multidrug resistance (MDR) remains a critical problem in the chemotherapy of patients with laryngeal cancer. This study aims to clarify the role and mechanisms of Notch1 signaling in MDR induced by hypoxia in laryngeal cancer cells.
Methods And Results:
Laryngeal carcinoma cells were cultured under normoxia or hypoxia. Notch1 expression was inhibited by small interfering RNA (siRNA). The mRNA expression of Notch1, Hes1, Hey1, MDR1 and survivin was analyzed by real-time PCR. The protein expression of Notch1, the Notch1 intracellular domain (N1ICD), MDR1/P-gp and survivin was analyzed by Western blotting. Current research has shown that hypoxia can upregulate Notch1 expression and Notch1 signaling activity. Furthermore, suppression of Notch1 expression effectively downregulated Notch1 signaling activity and the expression of the MDR and survivin genes in laryngeal cancer cells under hypoxic conditions (P < 0.05). The Cell Counting Kit-8 (CCK-8) assay results confirmed that the sensitivity of hypoxic laryngeal cancer cells to a variety of drugs could be upregulated by suppressing Notch1 expression (P < 0.05). Additionally, flow cytometry (FCM) showed that suppression of Notch1 expression significantly increased drug-induced apoptosis and intracellular rhodamine 123 (Rh123) accumulation in hypoxic laryngeal carcinoma cells (P < 0.05).
Conclusions:
Notch1 signalling could be regarded as a pivotal regulator of hypoxia-induced MDR in laryngeal cancer cells through the regulation of survivin-mediated apoptosis resistance and MDR1/P-gp-mediated drug transport.
Insights
Hypoxia promotes multidrug resistance (MDR) in laryngeal cancer by activating Notch1 signaling. Inhibiting Notch1 enhances drug sensitivity and apoptosis in hypoxic cancer cells, offering a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Laryngeal carcinoma is a common head and neck cancer.
- Multidrug resistance (MDR) poses a significant challenge in laryngeal cancer chemotherapy.
- Hypoxia is implicated in the development of MDR in various cancers.
Purpose of the Study:
- To investigate the role of Notch1 signaling in hypoxia-induced MDR in laryngeal cancer cells.
- To elucidate the underlying mechanisms by which Notch1 signaling contributes to MDR.
- To assess the therapeutic potential of targeting Notch1 signaling.
Main Methods:
- Laryngeal cancer cells were cultured under normoxic and hypoxic conditions.
- Notch1 expression was suppressed using small interfering RNA (siRNA).
- Gene and protein expression of Notch1, downstream targets, and MDR markers were analyzed using real-time PCR and Western blotting.
- Cell Counting Kit-8 (CCK-8) assays, flow cytometry (FCM), and rhodamine 123 (Rh123) accumulation assays were performed.
Main Results:
- Hypoxia was found to upregulate Notch1 expression and signaling activity in laryngeal cancer cells.
- Suppression of Notch1 significantly reduced Notch1 signaling, MDR1, and survivin expression under hypoxia.
- Inhibiting Notch1 increased drug sensitivity, promoted apoptosis, and enhanced intracellular drug accumulation in hypoxic cells.
Conclusions:
- Notch1 signaling is a key regulator of hypoxia-induced MDR in laryngeal cancer.
- Notch1 influences MDR by modulating survivin-mediated apoptosis resistance and MDR1/P-gp-mediated drug transport.
- Targeting Notch1 signaling presents a promising strategy to overcome MDR in laryngeal cancer.
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