ArticleThe Journal of biological chemistry2015
The Selective Degradation of Synaptic Connexin 43 Protein by Hypoxia-induced Autophagy Impairs Natural Killer Cell-mediated Tumor Cell Killing.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 99 citations in OpenAlex.
- NK cell-derived GZMB (granzyme B) suppresses glioblastoma radioresistance by blocking SDC1-mediated autophagosome maturation.Autophagy · 2026Article
- The Cx43-Mediated Autophagy Mechanism Influences Triple-Negative Breast Cancer Through the Regulation of Rab31.Cancers · 2025Article
- Tumor hypoxia shapes natural killer cell anticancer activities.Journal of molecular medicine (Berlin, Germany) · 2025Review
- Unveiling the Interplay Between Dendritic Cells and Natural Killer Cells as Key Players inJournal of immunology research · 2025Article
- Immune microenvironment regulation and clinical immunotherapy strategies of metastatic liver cancer.Frontiers in immunology · 2025Review
- Progressive Deactivation of Hydroxylases Controls Hypoxia-Inducible Factor-1α-Coordinated Cellular Adaptation to Graded Hypoxia.Research (Washington, D.C.) · 2025Article
- Effect of Hypoxia on Siglec-7 and Siglec-9 Receptors and Sialoglycan Ligands and Impact of Their Targeting on NK Cell Cytotoxicity.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Understanding the autophagic functions in cancer stem cell maintenance and therapy resistance.Expert reviews in molecular medicine · 2024Review
- Article
- Exploiting autophagy balance in T and NK cells as a new strategy to implement adoptive cell therapies.Molecular cancer · 2023Review
- NK cells are never alone: crosstalk and communication in tumour microenvironments.Molecular cancer · 2023Review
- Review
- Autophagy regulates anti-angiogenic property of lenvatinib in thyroid cancer.American journal of cancer research · 2023Article
- Crosstalk between autophagy and immune cell infiltration in the tumor microenvironment.Frontiers in medicine · 2023Review
- Physical activity prevents tumor metastasis through modulation of immune function.Frontiers in pharmacology · 2022Review
- The Effect of Hypoxia and Hypoxia-Associated Pathways in the Regulation of Antitumor Response: Friends or Foes?Frontiers in immunology · 2022Review
- Regulation of autophagy fires up the cold tumor microenvironment to improve cancer immunotherapy.Frontiers in immunology · 2022Review
- Emerging Role of Autophagy in the Development and Progression of Oral Squamous Cell Carcinoma.Cancers · 2021Review
- Understanding the Role of Autophagy in Cancer Formation and Progression Is a Real Opportunity to Treat and Cure Human Cancers.Cancers · 2021Review
- HIF-1α promotes the proliferation and migration of pulmonary arterial smooth muscle cells via activation of Cx43.Journal of cellular and molecular medicine · 2021Article
3 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although natural killer (NK) cells play an important role in the control of melanoma, hypoxic stress in the tumor microenvironment may impair NK-mediated tumor cell killing by mechanisms that are not fully understood. In this study, we investigated the effect of hypoxia on the expression and channel activity of connexin 43 (Cx43) in melanoma cells and its impact on their susceptibility to NK cell-mediated lysis. Our results demonstrated that hypoxic stress increases Cx43 expression in melanoma cells via hypoxia-inducible factor-1α (HIF-1α) transcriptional activity. Hypoxic cells displaying increased Cx43 expression were less susceptible to NK cell-mediated lysis compared with normoxic cells expressing a moderate level of Cx43. Conversely, when overexpressed in normoxic tumor cells, Cx43 improves their susceptibility to N cell-mediated killing. We show that the NK cell immune synapse formed with normoxic melanoma cells is more stable and contains a high level of gap-junctional Cx43 whereas that formed with hypoxic cells is less stable and contains a significant lower level of gap-junctional Cx43. We provide evidence that the activation of autophagy in hypoxic melanoma cells selectively degrades gap-junctional Cx43, leading to the destabilization of the immune synapse and the impairment of NK cell-mediated killing. Inhibition of autophagy by genetic or pharmacological approaches as well as expression of the non-degradable form of Cx43 significantly restore its accumulation at the immune synapse and improves N cell-mediated lysis of hypoxic melanoma cells. This study provides the first evidence that the hypoxic microenvironment negatively affects the immune surveillance of tumors by NK cells through the modulation of Cx43-mediated intercellular communications.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.