ClC-3 promotes paclitaxel resistance via modulating tubulins polymerization in ovarian cancer cells

Feng, Juntao; Peng, Zihan; Gao, Lvfen; Yang, Xiurou; Sun, Zele; Hou, Xiuying; Li, Enze; Zhu, Linyan; Yang, Haifeng

doi:10.1016/j.biopha.2021.111407

Cited by 11 publications

(20 citation statements)

References 39 publications

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“…It has been reported that ClC-3 contributes to PTX resistance in A549 NSCLC cells ( 17 ). ClC-3 was significantly upregulated in A549-PTX cells consistent with the results of previous studies ( 16 , 17 ). To verify the role of ClC-3 in PTX resistance, 4,4-diisothiocyanatostilbene-2,2-disulfonate (DIDS), a specific chloride channel inhibitor, was used.…”

Section: Resultssupporting

confidence: 92%

“…Chloride channels serve an important role in tumor drug resistance and have attracted wide attention. For example, ClC-3 increases the proportion of the free form of β-tubulin and decreases the proportion of the polymerized form of β-tubulin and finally decreases ovarian cancer cell sensitivity to PTX by interacting with SOX2 ( 16 ). ClC-3 participates in PTX resistance in A549 lung cancer cells through NF-κB signaling-dependent P-gp expression ( 17 ).…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating studies have suggested that ClC-3 is expressed in a number of cancer cells and serves a well-defined role in cell proliferation, apoptosis and metastasis (12)(13)(14)(15). Furthermore, abnormality of ClC-3 expression has been demonstrated to be associated with the development of drug resistance, including PTX, cisplatin and etoposide resistance, in various tumor cells (16)(17)(18)(19). However, the potential regulatory mechanism of ClC-3 in PTX resistance of NSCLC remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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SOX2 regulates paclitaxel resistance of A549 non‑small cell lung cancer cells via promoting transcription of ClC‑3

Huang

Wang

et al. 2022

Oncol Rep

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SOX2 regulates paclitaxel resistance of A549 non‑small cell lung cancer cells via promoting transcription of ClC‑3

Huang

Wang

et al. 2022

Oncol Rep

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“…In the ovarian cancer (OC) context, the majority of established chemoresistant cell lines are patient derived and have intrinsic resistance (30,31). Also, A2780 and IGROV1 PTX-induced variants are available, but these cell lines correspond to endometrioid OC subtype (32)(33)(34)(35)(36).…”

Section: Introductionmentioning

confidence: 99%

Generation of Two Paclitaxel-Resistant High-Grade Serous Carcinoma Cell Lines With Increased Expression of P-Glycoprotein

et al. 2021

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Debulking surgery followed by chemotherapy are the standard of care for high-grade serous carcinoma. After an initial good response to treatment, the majority of patients relapse with a chemoresistant profile, leading to a poor overall survival. Chemotherapy regimens used in high-grade serous carcinomas are based in a combination of classical chemotherapeutic drugs, namely, Carboplatin and Paclitaxel. The mechanisms underlying drug resistance and new drug discovery are crucial to improve patients’ survival. To uncover the molecular mechanisms of chemoresistance and test drugs capable of overcoming this resistant profile, it is fundamental to use good cellular models capable of mimicking the chemoresistant disease. Herein, we established two high-grade serous carcinoma cell lines with intrinsic resistance to Carboplatin and induced Paclitaxel resistance (OVCAR8 PTX R C and OVCAR8 PTX R P) derived from the OVCAR8 cell line. These two chemoresistant cell line variants acquired an enhanced resistance to Paclitaxel-induced cell death by increasing the drug efflux capacity, and this resistance was stable in long-term culture and following freeze/thaw cycles. The mechanism underlying Paclitaxel resistance resides in a significant increase in P-glycoprotein expression and, when this drug efflux pump was blocked with Verapamil, cells re-acquired Paclitaxel sensitivity. We generated two high-grade serous carcinoma cell lines, with a double-chemoresistant (Carboplatin and Paclitaxel) phenotype that mimics the majority of tumor recurrences in ovarian cancer context. This robust tool is suitable for preliminary drug testing towards the development of therapeutic strategies to overcome chemoresistance.

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“…Chloride channel 3 (CLCN3), one of the members of the chloride channel family that are voltage-gated, primarily regulates the homeostasis state of intercellular ions and the acidification of cellular compartments [6,7]. CLCN3 has been shown to function in cell proliferation, migration, and resistance to pharmacological treatment in glioma, ovarian cancer, and stomach adenocarcinoma cells [8][9][10]. Therefore, CLCN3 may function critically in the initiation and development of cancer.…”

Section: Ivyspring International Publishermentioning

confidence: 99%

HNRNPK/CLCN3 axis facilitates the progression of LUAD through CAF-tumor interaction

Li¹,

Yang

Ma³

et al. 2022

Int. J. Biol. Sci.

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Background: Chloride channel 3 (CLCN3) is regulated by transcription-coactivator, however, it is unclear which core transcription factor regulates CLCN3. The role of CLCN3 in lung adenocarcinoma (LUAD) is unexplored and the relationship between CLCN3 and tumor microenvironment is unknown. Methods: A 5′-biotin-labeled promoter probe of CLCN3 was used to pull down the promoter-binding transcription factor. Further study was investigated using LUAD samples, cell lines, and xenograft mice models, and the mechanism was explored. Results: CLCN3 was upregulated in human LUAD, and CLCN3 knockdown inhibited tumor proliferation and migration in vitro. Next, heterogeneous nuclear ribonucleoprotein K (HNRNPK) was first validated as a CLCN3 promoter-binding transcription factor. Mechanistically, HNRNPK knockdown suppressed the promoter activity of CLCN3, thus regulating CLCN3 expression at the transcriptional level, and the binding motif 'GCGAGG' and binding site '-538/-248 bp' were identified. Subsequently, the RNA-seq data illustrated that the primary functions of HNRNPK were similar to those of CLCN3. The results from in vitro and in vivo trials indicated that the expression and function of CLCN3 were regulated by HNRNPK. By isolating primary cancer-associated fibroblasts (CAFs) from human LUAD, we confirmed that decreased extracellular CLCN3 secretion induced by HNRNPK knockdown inhibited CAFs activation and TGF-β1 production, thus suppressing nuclear HNRNPK expression and LUAD progression in a feedback way. Furthermore, this phenomenon was rescued after the addition of TGF-β1, revealing that the HNRNPK/CLCN3 axis facilitated LUAD progression through intercellular interactions. Finally, we identified that CLCN3 and HNRNPK were upregulated and correlated with poor prognosis in LUAD patients. Conclusions: HNRNPK/CLCN3 axis facilitates the progression of LUAD through CAF-tumor interaction.

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ClC-3 promotes paclitaxel resistance via modulating tubulins polymerization in ovarian cancer cells

Cited by 11 publications

References 39 publications

SOX2 regulates paclitaxel resistance of A549 non‑small cell lung cancer cells via promoting transcription of ClC‑3

SOX2 regulates paclitaxel resistance of A549 non‑small cell lung cancer cells via promoting transcription of ClC‑3

Generation of Two Paclitaxel-Resistant High-Grade Serous Carcinoma Cell Lines With Increased Expression of P-Glycoprotein

HNRNPK/CLCN3 axis facilitates the progression of LUAD through CAF-tumor interaction

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