Role of β3 subunit of the GABA type A receptor in triple negative breast cancer proliferation, migration, and cell cycle progression

Bundy, J; Shaw, J; Hammel, M; Nguyen, J; Robbins, C; Mercier, I; Suryanarayanan, A

doi:10.1080/15384101.2024.2340912

Cell Cycle

2024

DOI: 10.1080/15384101.2024.2340912

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Role of β3 subunit of the GABA type A receptor in triple negative breast cancer proliferation, migration, and cell cycle progression

J Bundy,

J Shaw,

M Hammel

et al.

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2024

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Cited by 4 publications

References 42 publications

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The intersection of the nervous system and breast cancer

Liu,

Yin,

et al. 2024

Cancer Letters

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The intersection of the nervous system and breast cancer

Liu,

Yin,

et al. 2024

Cancer Letters

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GABA Type A receptors expressed in triple negative breast cancer cells mediate chloride ion flux

Bundy,

Ahmed,

Weller

et al. 2024

Front. Pharmacol.

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Triple negative breast cancer (TNBC) is known for its heterogeneous nature and aggressive onset, limited unresponsiveness to hormone therapies and immunotherapy as well as high likelihood of metastasis and recurrence. Since no targeted standard treatment options are available for TNBC, novel and effective therapeutic targets are urgently needed. Ion channels have emerged as possible novel therapeutic candidates for cancer therapy. We previously showed that GABAA β3 subunit are expressed at higher levels in TNBC cell lines than non-tumorigenic MCF10A cells. GABAA β3 subunit knockdown causes cell cycle arrest in TNBC cell lines via decreased cyclin D1 and increased p21 expression. However, it is not known if the upregulated GABAAR express at the cell-surface in TNBC and mediate Cl− flux. Cl− ions are known to play a role in cell-cycle progression in other cancers such as gastric cancer. Here, using surface biotinylation and (N-(Ethoxycarbonylmethyl)-6-Methoxyquinolinium Bromide) MQAE-dye based fluorescence quenching, we show that upregulated GABAAR are on the cell-surface in TNBC cell lines and mediate significantly higher chloride (Cl−) flux as compared to non-tumorigenic MCF10A cells. Moreover, this GABAAR mediated Cl− flux can be modulated by pharmacological agents and is decreased in TNBC cells with GABAA β3 subunit knockdown. Further, treatment of TNBC cells with bicuculline, a GABAAR antagonist reduced cell viability in TNBC cells Overall, these results point to an unexplored role of GABAAR mediated Cl− flux in TNBC.

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Multi-Omics Exploration of the Mechanism of Curcumol to Reduce Invasion and Metastasis of Nasopharyngeal Carcinoma by Inhibiting NCL/EBNA1-Mediated UBE2C Upregulation

Liu,

Wang,

Wang

et al. 2024

Biomolecules

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Nasopharyngeal carcinoma (NPC) is closely linked to Epstein–Barr virus (EBV) infection. Curcumae Rhizoma, a traditional Chinese herb, has shown antitumor effects, primarily through its component curcumol (Cur), which has been shown to reduce NPC cell invasion and migration by targeting nucleolin (NCL) and Epstein–Barr Virus Nuclear Antigen 1 (EBNA1). We constructed an EBV-positive NPC cell model using C666-1 cells and performed transcriptomics studies after treatment with curcumol, which revealed a significant enrichment of ubiquitin-mediated proteolysis, the PI3K-AKT and mTOR signaling pathways, cell cycle and apoptosis involved in tumor invasion and migration. To investigate the importance of NCL and EBNA1 in curcumol-resistant EBV-positive NPC, we performed a multi-omics study using short hairpin NCL (shNCL) and shEBNA1 EBV-positive NPC cells, and the proteomics results showed enrichment in complement and coagulation cascades and ubiquitin-mediated proteolysis signaling pathways. Here, we focused on ubiquitin-conjugating enzyme E2C (UBE2C), which plays an important role in the ubiquitin-mediated proteolysis signaling pathway. In addition, metabolomics revealed that UBE2C is highly associated with 4-Aminobutanoic acid (GABA). In vitro studies further validated the function of the key targets, suggesting that UBE2C plays an important role in NCL and EBNA1-mediated curcumol resistance to nasopharyngeal carcinoma invasion and metastasis.

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Role of β3 subunit of the GABA type A receptor in triple negative breast cancer proliferation, migration, and cell cycle progression

Cited by 4 publications

References 42 publications

The intersection of the nervous system and breast cancer

The intersection of the nervous system and breast cancer

GABA Type A receptors expressed in triple negative breast cancer cells mediate chloride ion flux

Multi-Omics Exploration of the Mechanism of Curcumol to Reduce Invasion and Metastasis of Nasopharyngeal Carcinoma by Inhibiting NCL/EBNA1-Mediated UBE2C Upregulation

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