Abstract
Background: Gemcitabine is widely used in the treatment of breast cancer (BC). However, the resistance to drugs remains a tough concern. The study explored the potential mechanism concerning gemcitabine resistance in triple-negative BC (TNBC) in vitro. Methods: TNBC cells (TNBCC) and gemcitabine-resistance cell lines (GRC) were used. We investigated the sensitivity to gemcitabine responsive to regulation of Nod-like receptor protein 3 (NLRP3) expression in TNBCC in different gemcitabine concentrations. RT-PCR checked NLRP3 mRNA expression and MTT assessed the cell cytotoxicity. Gemcitabine resistance was studied in GRC exposed to 0, 1, 3, 5 nm gemcitabine after GRC were treated with NLRP3 agonist Nigericin sodium salt (NSS) or antagonist CY-09. Epithelial-to-mesenchymal transition (EMT) biomarkers were evaluated via RT-PCR and inflammasome IL-1β, β-catenin content and GSK-3β activity were measured by ELISA methods. Last, we inactivated the signaling and examined the NLRP3, EMT mRNA expression by RT-PCR, IL-1β, β-catenin content and GSK-3β activity by ELISA and cell cytotoxicity through MTT. Results: NLRP3 up-regulation improved cell survival and reduced sensitivity to gemcitabine (P<0.05). NLRP3 had higher expression in GRC than TNBCC. GRC cell viability dropped as the gemcitabine concentration increased. NLRP3 up-regulation added to resistance to gemcitabine in GRC (P<0.05). NLRP3 agonist might induce EMT process, activate wnt/β-catenin signaling and IL-1β, while inactivation of wnt/β-catenin signaling could result in the inhibition of NLRP3, IL-1β and EMT as well as cell viability in GRC (P<0.05). Conclusion: NLRP3 could enhance resistance to gemcitabine via IL-1β/EMT/Wnt/β-catenin signaling, which suggested that NLRP3 antagonist CY-09 might be incorporated into gemcitabine treatment for TNBC.
Highlights
Gemcitabine has been widely introduced to the treatments of cancers and has been proved as a curative drug alone or combined with other drugs, including cisplatin [1,2,3]
It showed that highest cell viability was seen in agonist group with higher Nod-like receptor protein 3 (NLRP3) and lowest in antagonist group, suggesting that the higher expression of NLRP3, the less sensitive to different gemcitabine doses (P
breast cancer (BC) is mainly constituted of three subtypes, HR positive, human epidermal growth factor (HER2)-enriched and triple-negative BC (TNBC) according to immunohistochemical expression of the hormone receptors (HR): estrogen receptor (ER) and progesterone receptor (PR) as well as HER2 [22]
Summary
Gemcitabine has been widely introduced to the treatments of cancers and has been proved as a curative drug alone or combined with other drugs, including cisplatin [1,2,3]. Resistance to gemcitabine in cancer patients occurs commonly, which deters the curative effect [4]. Such situation hardly differs in breast cancer (BC). We investigated the sensitivity to gemcitabine responsive to regulation of Nod-like receptor protein 3 (NLRP3) expression in TNBCC in different gemcitabine concentrations. We inactivated the signaling and examined the NLRP3, EMT mRNA expression by RT-PCR, IL-1β, β-catenin content and GSK-3β activity by ELISA and cell cytotoxicity through MTT. Conclusion: NLRP3 could enhance resistance to gemcitabine via IL-1β/EMT/Wnt/β-catenin signaling, which suggested that NLRP3 antagonist CY-09 might be incorporated into gemcitabine treatment for TNBC
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