Reduced NADPH oxidase type 2 activity mediates sleep fragmentation-induced effects on TC1 tumors in mice
Jiamao Zheng1, Isaac Almendros1, Yang Wang1
1Section of Pediatric Sleep Medicine; Department of Pediatrics; Pritzker School of Medicine; Biological Sciences Division; The University of Chicago ; Chicago, Illinois, USA.
Abstract:
The molecular mechanisms underlying how sleep fragmentation (SF) influences cancer growth and progression remain largely elusive. Here, we present evidence that SF reduced ROS production by downregulating gp91 expression and activity in TC1 cell tumor associated macrophages (TAMs), while genetic ablation of phagocytic Nox2 activity increased tumor cell proliferation, motility, invasion, and extravasation in vitro. Importantly, the in vivo studies using immunocompetent syngeneic murine tumor models suggested that Nox2 deficiency mimics SF-induced TAMs infiltration and subsequent tumor growth and invasion. Taken together, these studies reveal that perturbed sleep could adversely affect innate immunity within the tumor by altering Nox2 expression and activity, and indicate that selective potentiation of Nox2 activity may present a novel therapeutic strategy in the treatment of cancer.
Insights
Sleep fragmentation impairs innate immunity by reducing Nox2 activity in tumor macrophages, promoting cancer progression. Enhancing Nox2 activity may offer a new cancer treatment strategy.
Area of Science:
- Immunology
- Oncology
- Sleep Science
Background:
- Sleep fragmentation's impact on cancer remains unclear.
- Tumor-associated macrophages (TAMs) play a role in cancer progression.
- Nox2 enzyme activity in TAMs is a potential regulator of cancer growth.
Purpose of the Study:
- To elucidate the molecular mechanisms by which sleep fragmentation affects cancer growth.
- To investigate the role of Nox2 in TAMs in the context of sleep fragmentation and cancer.
- To explore Nox2 activity as a potential therapeutic target for cancer.
Main Methods:
- Studied the effect of sleep fragmentation on ROS production and gp91 expression in TAMs.
- Utilized genetic ablation of Nox2 in tumor cells and TAMs.
- Employed in vitro assays for tumor cell proliferation, motility, invasion, and extravasation.
- Conducted in vivo studies using syngeneic murine tumor models.
Main Results:
- Sleep fragmentation reduced ROS production by downregulating gp91 expression and activity in TAMs.
- Genetic ablation of Nox2 increased tumor cell proliferation, motility, invasion, and extravasation in vitro.
- Nox2 deficiency in vivo mimicked sleep fragmentation-induced TAMs infiltration, promoting tumor growth and invasion.
Conclusions:
- Perturbed sleep adversely affects innate immunity within tumors by altering Nox2 expression and activity in TAMs.
- Selective potentiation of Nox2 activity may represent a novel therapeutic strategy for cancer treatment.
