ArticleProceedings of the National Academy of Sciences of the United States of America2022
Lysosomal inhibition sensitizes TMEM16A-expressing cancer cells to chemotherapy.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 36 citations in OpenAlex.
- Targeting lysosome-dependent cell death in cancer: towards therapeutic strategies.Biomarker research · 2026Review
- Mechanistic insights into the dynamics of plasma membrane repair in cancer.Molecular biology reports · 2025Review
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- Epidrug screening identifies type I PRMT inhibitors as modulators of lysosomal exocytosis and drug sensitivity in cancers.Cell death & disease · 2025Article
- Review
- Lysosomes: guardians and healers within cells- multifaceted perspective and outlook from injury repair to disease treatment.Cancer cell international · 2025Review
- Lysosomal-Mitochondrial Interaction Promotes Tumor Growth in Squamous Cell Carcinoma of the Head and Neck.Molecular cancer research : MCR · 2025Article
- High Ano1 expression as key driver of resistance to radiation and cisplatin in HPV-negative head and neck squamous cell carcinoma.Scientific reports · 2025Article
- A Narrative Review of Prognostic Gene Signatures in Oral Squamous Cell Carcinoma Using LASSO Cox Regression.Biomedicines · 2025Review
- Review
- Chromatin remodeling-driven autophagy activation induces cisplatin resistance in oral squamous cell carcinoma.Cell death & disease · 2024Article
- Review
- p90RSK pathway inhibition synergizes with cisplatin in TMEM16A overexpressing head and neck cancer.BMC cancer · 2024Article
- The dual role of autophagy in the regulation of cancer treatment.Amino acids · 2024Review
- Article
- Safety of Immunomodulatory Systemic Therapies Used in the Management of Immune-Related Cutaneous Adverse Events.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Ion Channels as Potential Tools for the Diagnosis, Prognosis, and Treatment of HPV-Associated Cancers.Cells · 2023Review
- Review
- Co-delivery of doxorubicin and hydroxychloroquine via chitosan/alginate nanoparticles for blocking autophagy and enhancing chemotherapy in breast cancer therapy.Frontiers in pharmacology · 2023Article
- Article
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Squamous cell carcinoma of the head and neck (SCCHN) is a devastating disease that continues to have low cure rates despite the recent advances in therapies. Cisplatin is the most used chemotherapy agent, and treatment failure is largely driven by resistance to this drug. Amplification of chromosomal band 11q13 occurs in ∼30% of SCCHN tumors. This region harbors the ANO1 gene that encodes the TMEM16A ion channel, which is responsible for calcium-activated chloride transport in epithelial tissues. TMEM16A overexpression is associated with cisplatin resistance, and high TMEM16A levels correlate with decreased survival. However, the mechanistic underpinning of this effect remains unknown. Lysosomal biogenesis and exocytosis have been implicated in cancer because of their roles in the clearance of damaged organelles and exocytosis of chemotherapeutic drugs and toxins. Here, we show that TMEM16A overexpression promotes lysosomal biogenesis and exocytosis, which is consistent with the expulsion of intracellular cisplatin. Using a combination of genetic and pharmacologic approaches, we find that TMEM16A promotes lysosomal flux in a manner that requires reactive oxygen species, TRPML1, and the activation of the β-catenin–melanocyte-inducing transcription factor pathway. The lysosomal inhibitor hydroxychloroquine (HCQ) synergizes with cisplatin in killing SCCHN cells in vitro. Using a murine model of SCCHN, we show that HCQ and cisplatin retard the growth of cisplatin-resistant patient-derived xenografts in vivo. We propose that TMEM16A enables cell survival by the up-regulation of lysosomal sequestration and exocytosis of the cytotoxic drugs. These results uncover a model of treatment for resistance in cancer, its reversal, and a role for TMEM16A.
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