The Role of Autophagy in Salivary Gland Homeostasis and Stress Responses

Morgan‐Bathke, Maria; Lin, H. Helen; Ann, David K.; Limesand, Kirsten H.

doi:10.1177/0022034515590796

Cited by 19 publications

(16 citation statements)

References 69 publications

(83 reference statements)

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“…We have hypothesized that induction of autophagy in the LG may help reduce LG inflammation by clearing accumulated proteins and damaged secretory vesicles, consistent with findings in salivary gland acini. 64 Rapa caused a significant decrease in Akt3 gene expression levels ( Fig. 7 A), inhibition of which induces autophagy, 65 but did not significantly alter expression of ulk1 ( Fig.…”

Section: Resultsmentioning

confidence: 92%

Rapamycin Eye Drops Suppress Lacrimal Gland Inflammation In a Murine Model of Sjögren's Syndrome

Shah

Edman

Janga

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeTo evaluate the efficacy of topical rapamycin in treating autoimmune dacryoadenitis in a mouse model of Sjögren's syndrome.MethodsWe developed rapamycin in a poly(ethylene glycol)-distearoyl phosphatidylethanolamine (PEG-DSPE) micelle formulation to maintain solubility. Rapamycin or PEG-DSPE eye drops (vehicle) were administered in a well-established Sjögren's syndrome disease model, the male nonobese diabetic (NOD) mice, twice daily for 12 weeks starting at 8 weeks of age. Mouse tear fluid was collected and tear Cathepsin S, a putative tear biomarker for Sjögren's syndrome, was measured. Lacrimal glands were retrieved for histological evaluation, and quantitative real-time PCR of genes associated with Sjögren's syndrome pathogenesis. Tear secretion was measured using phenol red threads, and corneal fluorescein staining was used to assess corneal integrity.ResultsLymphocytic infiltration of lacrimal glands from rapamycin-treated mice was significantly (P = 0.0001) reduced by 3.8-fold relative to vehicle-treated mice after 12 weeks of treatment. Rapamycin, but not vehicle, treatment increased tear secretion and decreased corneal fluorescein staining after 12 weeks. In rapamycin-treated mice, Cathepsin S activity was significantly reduced by 3.75-fold in tears (P < 0.0001) and 1.68-fold in lacrimal gland lysates (P = 0.003) relative to vehicle-treated mice. Rapamycin significantly altered the expression of several genes linked to Sjögren's syndrome pathogenesis, including major histocompatibility complex II, TNF-α, IFN-γ, and IL-12a, as well as Akt3, an effector of autophagy.ConclusionsOur findings suggest that topical rapamycin reduces autoimmune-mediated lacrimal gland inflammation while improving ocular surface integrity and tear secretion, and thus has potential for treating Sjögren's syndrome–associated dry eye.

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Section: Resultsmentioning

confidence: 92%

Rapamycin Eye Drops Suppress Lacrimal Gland Inflammation In a Murine Model of Sjögren's Syndrome

Shah

Edman

Janga

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…Autophagy is a highly conserved process in eukaryotes in which the cytoplasm, including excess or aberrant organelles, is sequestered into double-membrane vesicles and delivered to the degradative organelle, the lysosome/vacuole, for breakdown ( 35 ), leading to the eventual recycling of the resulting macromolecules. While under pathological conditions, autophagy contributes to the turnover of long-lived proteins and elimination of damaged or aged organelles to maintain cell homeostasis ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of autophagy attenuated curcumol‑induced apoptosis in MG‑63 human osteosarcoma cells via Janus kinase signaling pathway

Zhang

Wang

2017

Oncol Lett

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The present study aimed to investigate whether autophagy was triggered by curcumol and to explore the association between autophagy and apoptosis of MG-63 cells and the underlying mechanism. MG-63 cells were cultured in vitro. An MTT assay was performed to evaluate the proliferation inhibition of the MG-63 osteosarcoma cell line by curcumol. Fluorescein isothiocyanate-Annexin V/propidium iodide staining flow cytometry was performed to analyze the apoptotic rate of cells. The morphological alterations of cell nuclei were evaluated by Hoechst 33258 viable cell staining. The effects of autophagy in cells was investigated by green fluorescent protein (GFP)-light chain 3 (LC3) transfection and using a fluorescence microscope. The expression levels of LC3II, LC3I and cleaved caspase-3 and Janus kinase (JNK) signaling pathway activation were determined by western blot analysis. Cell proliferation was inhibited by curcumol in a dose- and time-dependent manner. Curcumol induced apoptosis by the caspase-dependent signaling pathway in MG-63 cells. The present study demonstrated that curcumol could induce autophagy of MG-63 cells, which was evaluated by transmission electron microscopy. Compared with the curcumol treatment alone group, the GFP-LC3-transfected green fluorescence plasmids and the LC3II/LC3I levels in cells of the curcumol and chloroquine (CQ) treatment group were upregulated, and the apoptotic ratio was downregulated following pretreatment with autophagy inhibitor CQ for 1 h. Furthermore, curcumol treatment induced phosphorylation of the JNK signaling pathway. Of note, pretreatment with the JNK inhibitor, SP600125, decreased the rates of autophagy and apoptosis, suggesting a crucial role served by the JNK signaling pathway in the activation of autophagy by curcumol. Taken together, the results of the present study suggested that activation of the JNK signaling pathway was involved in curcumol-induced autophagy. Curcumol is a novel drug for chemotherapeutic combination therapy. Curcumol demonstrated potential antitumor activities in MG-63 cells and may be used as a novel effective reagent in the treatment of osteosarcoma.

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“…These results suggest that autophagy inhibition might be effectively used in combination with LPLI for OSCC therapy. Autophagy is induced in the salivary gland in response to radiation to balance proliferation and apoptosis [ 38 ]. Further in vivo studies are required to determine the effectiveness and potential side effects of a combined treatment with LPLI and CQ for OSCC patients.…”

Section: Discussionmentioning

confidence: 99%

RelA-Mediated BECN1 Expression Is Required for Reactive Oxygen Species-Induced Autophagy in Oral Cancer Cells Exposed to Low-Power Laser Irradiation

Shu¹,

Chang²,

Wu³

et al. 2016

PLoS ONE

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Low-power laser irradiation (LPLI) is a non-invasive and safe method for cancer treatment that alters a variety of physiological processes in the cells. Autophagy can play either a cytoprotective role or a detrimental role in cancer cells exposed to stress. The detailed mechanisms of autophagy and its role on cytotoxicity in oral cancer cells exposed to LPLI remain unclear. In this study, we showed that LPLI at 810 nm with energy density 60 J/cm2 increased the number of microtubule associated protein 1 light chain 3 (MAP1LC3) puncta and increased autophagic flux in oral cancer cells. Moreover, reactive oxygen species (ROS) production was induced, which increased RelA transcriptional activity and beclin 1 (BECN1) expression in oral cancer cells irradiated with LPLI. Furthermore, ROS scavenger or knockdown of RelA diminished LPLI-induced BECN1 expression and MAP1LC3-II conversion. In addition, pharmacological and genetic ablation of autophagy significantly enhanced the effects of LPLI-induced apoptosis in oral cancer cells. These results suggest that autophagy may be a resistant mechanism for LPLI-induced apoptosis in oral cancer cells.

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The Role of Autophagy in Salivary Gland Homeostasis and Stress Responses

Cited by 19 publications

References 69 publications

Rapamycin Eye Drops Suppress Lacrimal Gland Inflammation In a Murine Model of Sjögren's Syndrome

Rapamycin Eye Drops Suppress Lacrimal Gland Inflammation In a Murine Model of Sjögren's Syndrome

Inhibition of autophagy attenuated curcumol‑induced apoptosis in MG‑63 human osteosarcoma cells via Janus kinase signaling pathway

RelA-Mediated BECN1 Expression Is Required for Reactive Oxygen Species-Induced Autophagy in Oral Cancer Cells Exposed to Low-Power Laser Irradiation

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