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ANO6 Confers Paclitaxel Resistance by Targeting Ferroptosis in Cervical Cancer
Yanming Cao1, Yuping Peng1, Jian Shen2
1Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Abstract:
Paclitaxel (PTX) resistance limits cervical cancer therapy. Ferroptosis suppression via GPX4 and redox remodeling has emerged as a resistance mechanism, but upstream regulators remain unclear. To determine whether ANO6 drives PTX resistance by inhibiting ferroptosis and to define the ANO6-GPX4 axis mechanistically and therapeutically. Transcriptomic analyses, immunohistochemistry on clinical specimens, and cervical cancer cell models with gain/loss of ANO6 were combined with ferroptosis assays, mitochondrial imaging, apoptosis/viability assays, and Co-IP/CHX chase to assess ANO6-GPX4 interaction and stability. GPX4 transcriptional control was probed by ChIP-qPCR and dual-luciferase. PTX sensitivity was tested in vitro and in xenografts, with or without the ferroptosis inducer RSL3. ANO6 was overexpressed in cervical cancer and associated with worse prognosis. ANO6 knockdown reduced GPX4, SLC7A11, and NRF2, increased ACSL4, elevated lipid peroxidation and iron load, disrupted mitochondrial integrity, and heightened PTX cytotoxicity; ANO6 overexpression had opposite effects. ANO6 physically associated with GPX4 and preserved its protein stability; NRF2 enhanced GPX4 promoter activity, supporting a dual (post-translational/transcriptional) maintenance of GPX4 under ANO6 control. In PTX-resistant cells, ANO6 was upregulated; its depletion restored ferroptosis and PTX sensitivity, whereas GPX4 overexpression rescued resistance. In vivo, ANO6 overexpression promoted tumor growth and PTX resistance, while PTX + RSL3 synergistically suppressed tumors and reversed GPX4-axis signaling. ANO6 confers PTX resistance by sustaining GPX4-dependent ferroptosis evasion and mitochondrial homeostasis. Targeting the ANO-GPX4 axis, alone or combined with ferroptosis induction, may improve chemotherapy sensitivity in cervical cancer.
Insights
Anoctamin 6 (ANO6) drives paclitaxel resistance in cervical cancer by preventing ferroptosis through the ANO6-GPX4 axis. Targeting this axis may improve chemotherapy effectiveness.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Paclitaxel (PTX) resistance is a major challenge in cervical cancer treatment.
- Ferroptosis suppression, mediated by GPX4, is a known mechanism of PTX resistance.
- Upstream regulators of ferroptosis suppression in this context remain largely unknown.
Purpose of the Study:
- To investigate the role of Anoctamin 6 (ANO6) in paclitaxel resistance in cervical cancer.
- To elucidate the mechanistic link between ANO6, GPX4, and ferroptosis.
- To explore the therapeutic potential of targeting the ANO6-GPX4 axis.
Main Methods:
- Transcriptomic analysis and immunohistochemistry on clinical cervical cancer specimens.
- In vitro studies using cervical cancer cell models with manipulated ANO6 expression.
- Ferroptosis, mitochondrial, apoptosis, and viability assays.
- Co-immunoprecipitation and CHX chase assays to assess protein-protein interactions and stability.
- Chromatin immunoprecipitation-qPCR and dual-luciferase assays for transcriptional regulation.
- In vitro and in vivo (xenograft) testing of PTX sensitivity, alone and with the ferroptosis inducer RSL3.
Main Results:
- ANO6 was overexpressed in cervical cancer and correlated with poor prognosis.
- ANO6 knockdown sensitized cells to PTX by increasing ferroptosis markers and decreasing GPX4 and NRF2.
- ANO6 physically interacted with GPX4, stabilizing its protein and promoting ferroptosis evasion.
- ANO6 overexpression conferred PTX resistance, while its depletion restored sensitivity.
- Combined PTX and RSL3 treatment synergistically suppressed tumors in vivo and reversed ANO6-mediated signaling.
Conclusions:
- ANO6 promotes paclitaxel resistance in cervical cancer by maintaining GPX4-dependent ferroptosis suppression and mitochondrial homeostasis.
- The ANO6-GPX4 axis represents a novel therapeutic target.
- Combination therapy involving ferroptosis induction may enhance chemotherapy efficacy in cervical cancer.
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