FoxO1 as a Regulator of Aquaporin 5 Expression in the Salivary Gland

Lee, So Mi; Lee, S W; Kang, Mingyu; Choi, Jae-Sun; Park, K; Byun, Jun‐Kyu; Kim, D Y

doi:10.1177/00220345211003490

Cited by 9 publications

(5 citation statements)

References 31 publications

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“…AQP5 is embedded in the lipid bilayer of the cytoplasmic membrane and forms a tetramer. Due to the unique structure of AQP5, it plays an important role in the transmembrane transport of water and small molecular compounds [ 28 ]. Previous studies have reported that AQP5 cooperates with the calcium channel TRPV4 to regulate cell volume [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination

Zhao

Bie

et al. 2022

J Exp Clin Cancer Res

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Background Cancer stem cells (CSCs) are regarded as the "seed cells" for tumorigenesis, metastasis, recurrence and drug resistance. However, specific surface markers of CSCs of different origins have not been documented. Methods Single-cell sequencing was used to analyze the highly expressed genes in cancer stem cells of gastric cancer patients, and it was verified that AQP5 was specifically highly expressed in gastric cancer stem cells (GC-CSCs) in vivo and in vitro. The effect of AQP5-promoting LGR5 on the malignant biological function of GC-CSCs was investigated. The mechanism by which AQP5 affects GC-CSCs was explored through transcriptome sequencing, proteomic detection, mass spectrometry, etc. Results We report the identification and validation of AQP5 as a potentially specific surface marker of GC-CSCs. AQP5 was significantly upregulated in CSCs isolated from gastric cancer patients and in spheroid cells, and AQP5 was coexpressed with the canonical stem marker LGR5. Biologically, AQP5 promoted the sphere formation, proliferation, migration and invasion of GC cells in vitro and enhanced tumorigenesis in vivo. Furthermore, AQP5 coordinated with LGR5 and synergistically promoted the tumorigenesis of GC-CSCs. At the mechanistic level, AQP5 activated autophagy by inducing the LC3I/LC3II transformation in GC-CSCs, which was crucial for the biological functions of AQP5. Finally, we demonstrated that AQP5 recruited the E3 ligase TRIM21 to the key autophagy protein ULK1 and induced the K63-mediated ubiquitination of ULK1. Conclusions We elucidate a novel surface marker, AQP5, which is specifically expressed by GC-CSCs. Furthermore, our study creates a link between AQP5 and LGR5 and highlights the necessity of targeting both surface markers simultaneously as a promising approach for the treatment of gastric cancer patients.

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Section: Discussionmentioning

confidence: 99%

AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination

Zhao

Bie

et al. 2022

J Exp Clin Cancer Res

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“…It was recently reported that FOXO1 directly regulates AQP5 expression in salivary gland acinar cells. FOXO1 is a direct regulator of AQP5 expression in salivary gland acinar cells through its interaction with the promoter region of AQP5 [69]. AQP5 is the most important protein for salivation since it directly mediates the transcellular movement of water from the basal to apical or lumen side of acinar cells [70].…”

Section: Discussionmentioning

confidence: 99%

Polydatin Alleviates Diabetes-Induced Hyposalivation through Anti-Glycation Activity in db/db Mouse

et al. 2021

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Polydatin (resveratrol-3-O-β-mono-D-glucoside) is a polyphenol that can be easily accessed from peanuts, grapes, and red wine, and is known to have antiglycation, antioxidant, and anti-inflammatory effects. Diabetes mellitus is a very common disease, and diabetic complications are very common complications. The dry mouth symptom is one of the most common oral complaints in patients with diabetes mellitus. Diabetes mellitus is thought to promote hyposalivation. In this study, we aimed to investigate the improvement effect of polydatin on diabetes-induced hyposalivation in db/db mouse model of type 2 diabetes. We examined salivary flow rate, TUNEL assay, PAS staining, and immunohistochemical staining for AGEs, RAGE, HMGB1, 8-OHdG, and AQP5 to evaluate the efficacy of polydatin in the submandibular salivary gland. Diabetic db/db mice had a decreased salivary flow rate and salivary gland weight. The salivary gland of the vehicle-treated db/db mice showed an increased apoptotic cell injury. The AGEs were highly accumulated, and its receptor, RAGE expression was also enhanced. Expressions of HMGB1, an oxidative cell damage marker, and 8-OHdG, an oxidative DNA damage marker, increased greatly. However, polydatin ameliorated this hypofunction of the salivary gland and inhibited diabetes-related salivary cell injury. Furthermore, polydatin improved mucin accumulation, which is used as a damage marker for salivary gland acinar cells, and decreased expression of water channel AQP5 was improved by polydatin. In conclusion, polydatin has a potent protective effect on diabetes-related salivary gland hypofunction through its antioxidant and anti-glycation activities, and its AQP5 upregulation. This result suggests the possibility of the use of polydatin as a therapeutic drug to improve hyposalivation caused by diabetes.

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“…Interestingly, the only data on aquaporins and the FOXO family were obtained on salivary gland cells where AQP5 was found to be regulated by FOXO1 [147]. However, in breast cancer the FOXO family is down-regulated, while AQP5 is up-regulated and positively correlated with its malignancy [30,54,148].…”

Section: Foxomentioning

confidence: 99%

The Involvement of Peroxiporins and Antioxidant Transcription Factors in Breast Cancer Therapy Resistance

Milković,

Mlinarić,

Lučić

et al. 2023

Cancers

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Breast cancer is still the leading cause of death in women of all ages. The reason for this is therapy resistance, which leads to the progression of the disease and the formation of metastases. Multidrug resistance (MDR) is a multifactorial process that leads to therapy failure. MDR involves multiple processes and many signaling pathways that support each other, making it difficult to overcome once established. Here, we discuss cellular-oxidative-stress-modulating factors focusing on transcription factors NRF2, FOXO family, and peroxiporins, as well as their possible contribution to MDR. This is significant because oxidative stress is a consequence of radiotherapy, chemotherapy, and immunotherapy, and the activation of detoxification pathways could modulate the cellular response to therapy and could support MDR. These proteins are not directly responsible for MDR, but they support the survival of cancer cells under stress conditions.

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FoxO1 as a Regulator of Aquaporin 5 Expression in the Salivary Gland

Cited by 9 publications

References 31 publications

AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination

AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination

Polydatin Alleviates Diabetes-Induced Hyposalivation through Anti-Glycation Activity in db/db Mouse

The Involvement of Peroxiporins and Antioxidant Transcription Factors in Breast Cancer Therapy Resistance

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