CLDN1 Increases Drug Resistance of Non-Small Cell Lung Cancer by Activating Autophagy via Up-Regulation of ULK1 Phosphorylation

Zhao, Zhen; Li, Jing; Jiang, Yan; Xu, Wen; Li, Xin; Jing, Weili

doi:10.12659/msm.904177

Cited by 30 publications

(26 citation statements)

References 37 publications

(41 reference statements)

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“…Recently, it has been reported that the autophagosome marker Atg16L colocalizes with CLDN5 in endocytosed vesicles transported across the cells, indicating that the process of tight junction remodeling involves the regulation of autophagy [53]. Zhao Z. et al discovered that CLDN1 regulated drug resistance by promoting autophagy, which was mediated by ULK1 phosphorylation in non-small cell lung cancer [54]. In addition, J. Kim et al reported that CLDN1 functions as an autophagy stimulator to increase autophagy flux and accelerate the degradation of SQSTM1/p62 [55].…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor β inhibits breast cancer cells migration and invasion through CLDN6-mediated autophagy

Song

Dong

et al. 2019

J Exp Clin Cancer Res

106

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Background Estrogen receptor β (ERβ) has been reported to play an anti-cancer role in breast cancer, but the regulatory mechanism by which ERβ exerts this effect is not clear. Claudin-6 (CLDN6), a tight junction protein, acts as a tumor suppressor gene in breast cancer. Our previous studies have found that 17β-estradiol (E2) induces CLDN6 expression and inhibits MCF-7 cell migration and invasion, but the underlying molecular mechanisms are still unclear. In this study, we aimed to investigate the role of ERβ in this process and the regulatory mechanisms involved. Methods Polymerase chain reaction (PCR) and western blot were used to characterize the effect of E2 on the expression of CLDN6 in breast cancer cells. Chromatin immunoprecipitation (ChIP) assays were carried out to confirm the interaction between ERβ and CLDN6. Dual luciferase reporter assays were used to detect the regulatory role of ERβ on the promoter activity of CLDN6. Wound healing and Transwell assays were used to examine the migration and invasion of breast cancer cells. Western blot, immunofluorescence and transmission electron microscopy (TEM) were performed to detect autophagy. Xenograft mouse models were used to explore the regulatory effect of the CLDN6-beclin1 axis on breast cancer metastasis. Immunohistochemistry (IHC) was used to detect ERβ/CLDN6/beclin1 expression in breast cancer patient samples. Results Here, E2 upregulated the expression of CLDN6, which was mediated by ERβ. ERβ regulated CLDN6 expression at the transcriptional level. ERβ inhibited the migration and invasion of breast cancer cells through CLDN6. Interestingly, this effect was associated with CLDN6-induced autophagy. CLDN6 positively regulated the expression of beclin1, which is a key regulator of autophagy. Beclin1 knockdown reversed CLDN6-induced autophagy and the inhibitory effect of CLDN6 on breast cancer metastasis. Moreover, ERβ and CLDN6 were positively correlated, and the expression of CLDN6 was positively correlated with beclin1 in breast cancer tissues. Conclusion Overall, this is the first study to demonstrate that the inhibitory effect of ERβ on the migration and invasion of breast cancer cells was mediated by CLDN6, which induced the beclin1-dependent autophagic cascade. Electronic supplementary material The online version of this article (10.1186/s13046-019-1359-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Estrogen receptor β inhibits breast cancer cells migration and invasion through CLDN6-mediated autophagy

Song

Dong

et al. 2019

J Exp Clin Cancer Res

106

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“…Another gene was CLDN1, which was upregulated more than 1.8-fold in both cell lines. CLDN1 is a member of the tight junction family of genes and has attracted attention because of its altered expression in many cancers as well as its association with cellular properties (invasion, migration) indicating cancer progression, which are normalized upon its knockdown in breast and lung cancer cells 45,46 . Further, PRMT6 was downregulated more than 1.7-fold in both cell lines.…”

Section: Discussionmentioning

confidence: 99%

Optineurin downregulation induces endoplasmic reticulum stress, chaperone-mediated autophagy, and apoptosis in pancreatic cancer cells

et al. 2019

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Pancreatic ductal adenocarcinoma (PDAC) shows a high level of basal autophagy. Here we investigated the role of optineurin (OPTN) in PDAC cell lines, which is a prominent member of the autophagy system. To that purpose, mining of publically available databases showed that OPTN is highly expressed in PDAC and that high levels of expression are related to reduced survival. Therefore, the role of OPTN on proliferation, migration, and colony formation was investigated by transient knockdown in Miapaca, BXPC3, and Suit2-007 human PDAC cells. Furthermore, gene expression modulation in response to OPTN knockdown was assessed by microarray. The influence on cell cycle distribution and cell death signaling cascades was followed by FACS, assays for apoptosis, RT-PCR, and western blot. Finally, autophagy and ROS induction were screened by acridine orange and DCFH-DA fluorescent staining respectively. OPTN knockdown caused significant inhibition of colony formation, increased migration and no significant effect on proliferation in Miapaca, BXPC3 and Suit2-007 cells. The microarray showed modulation of 293 genes in Miapaca versus 302 in Suit2-007 cells, of which 52 genes overlapped. Activated common pathways included the ER stress response and chaperone-mediated autophagy, which was confirmed at mRNA and protein levels. Apoptosis was activated as shown by increased levels of cleaved PARP, Annexin V binding and nuclear fragmentation. OPTN knockdown caused no increased vacuole formation as assessed by acridine orange. Also, there was only marginally increased ROS production. Combination of OPTN knockdown with the autophagy inducer erufosine or LY294002, an inhibitor of autophagy, showed additive effects, which led us to hypothesize that they address different pathways. In conclusion, OPTN knockdown was related to activation of ER stress response and chaperone-mediated autophagy, which tend to confine the damage caused by OPTN knockdown and thus question its value for PDAC therapy.

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“…It has been reported that overexpression of ULK1 is inversely related to the prognosis of various tumors, such as colon cancer, breast cancer, lung cancer, nasopharyngeal cancer, and esophageal cancer [136]. The knockdown of ULK1 in NSCLC cells induces an increase in apoptosis and makes them more sensitive to cisplatin [209]. SBI0206965, a selective inhibitor of ULK1, can significantly reduce the cell survival of cisplatin-resistant NSCLC cells by decreasing the conversion of LC3 I to LC3 II, upregulating the expression of autophagy substrate P62, and inhibiting the progress of autophagy.…”

Section: Small Molecule Drugs Targeting Ulk Reverse Tumor Resistancementioning

confidence: 99%

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

Liu

Liao

et al. 2020

Cancers

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The difficulty of early diagnosis and the development of drug resistance are two major barriers to the successful treatment of cancer. Autophagy plays a crucial role in several cellular functions, and its dysregulation is associated with both tumorigenesis and drug resistance. Unc-51-like kinase 1 (ULK1) is a serine/threonine kinase that participates in the initiation of autophagy. Many studies have indicated that compounds that directly or indirectly target ULK1 could be used for tumor therapy. However, reports of the therapeutic effects of these compounds have come to conflicting conclusions. In this work, we reviewed recent studies related to the effects of ULK1 on the regulation of autophagy and the development of drug resistance in cancers, with the aim of clarifying the mechanistic underpinnings of this therapeutic target.

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CLDN1 Increases Drug Resistance of Non-Small Cell Lung Cancer by Activating Autophagy via Up-Regulation of ULK1 Phosphorylation

Cited by 30 publications

References 37 publications

Estrogen receptor β inhibits breast cancer cells migration and invasion through CLDN6-mediated autophagy

Estrogen receptor β inhibits breast cancer cells migration and invasion through CLDN6-mediated autophagy

Optineurin downregulation induces endoplasmic reticulum stress, chaperone-mediated autophagy, and apoptosis in pancreatic cancer cells

A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer

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