Claudin-18 inhibits cell proliferation and motility mediated by inhibition of phosphorylation of PDK1 and Akt in human lung adenocarcinoma A549 cells

Shimobaba, Shun; Taga, Saeko; Akizuki, Risa; Hichino, Asami; Endo, Shunsuke; Matsunaga, Toshiyuki; Watanabe, Ryoji; Yamaguchi, Masahiko; Yamazaki, Yoji; Sugatani, Junko; Ikari, Akira

doi:10.1016/j.bbamcr.2016.02.015

Cited by 40 publications

(37 citation statements)

References 41 publications

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“…In the stomach, which was also enlarged, we observed expansion of the gastric mucosa (Supplemental Figure 4) with Figure 6E) indicates that the CLDN18.1 isoform is downregulated in LuAd. Consistent with these findings, overexpression of CLDN18.1 was found to suppress abnormal proliferation and motility of A549 cells, a human LuAd cell line, via inhibition of PI3K/PDK1/Akt signaling (75). Therapeutic targeting of CLDN18 should therefore take into account the specific isoform that is altered in a particular subtype of LuAd.…”

Section: Discussionsupporting

confidence: 54%

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

Zhou¹,

Flodby²,

Luo³

et al. 2018

Journal of Clinical Investigation

125

116

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Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18 -/-AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18 -/-mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.

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Section: Discussionsupporting

confidence: 54%

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

Zhou¹,

Flodby²,

Luo³

et al. 2018

Journal of Clinical Investigation

125

116

View full text Add to dashboard Cite

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“…Interestingly, studies in Cldn18 −/− mice showed that AKT phosphorylation is also regulated by CLDN18 in non-malignant cells from both embryonic lungs (Figure 4B) and adult AT2 cells (Supplemental Table 5), suggesting that the CLDN18.1/AKT axis is operative in normal cells and may therefore be involved in tumor initiation associated with loss of CLDN18. These results are consistent with inhibition of AKT recently observed in A549 LuAd cells upon CLDN18.1 expression (15). …”

Section: Discussionsupporting

confidence: 93%

“…CLDN18.1 is emerging as a tumor suppressor in lung alveolar epithelial cells (15,18). Compared to normal tissue, LuAd displays increased CLDN18.1 promoter methylation (Figure 1) and decreased mRNA expression (Figure 1 and Ref.…”

Section: Discussionmentioning

confidence: 99%

“…While our recent work demonstrates direct interaction between CLDN18.1 and YAP (18), the present results and those of Shimobaba et.al. (15) suggest that additional signaling pathways are involved in the tumor suppressor activity of CLDN18.1, including TAZ, IGF-1R and AKT.…”

Section: Discussionmentioning

confidence: 99%

“…Another splicing isoform, CLDN18.2 , is normally expressed in stomach (10,11) and ectopically in pancreatic, esophageal, ovarian and lung cancers (12–14). Whereas numerous studies have focused on ectopic expression of CLDN18.2 , investigation of CLDN18.1 in cancer has been limited (15,16). Using Cldn18 −/− mice, in which both Cldn18.1 and Cldn18.2 isoforms are globally deleted, we recently assigned a role for CLDN18 in regulating not only epithelial permeability and ion transport, but also proliferation of lung alveolar epithelial type II (AT2) cells, organ size and tumorigenicity (17,18).…”

Section: Introductionmentioning

confidence: 99%

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CLDN18.1 attenuates malignancy and related signaling pathways of lung adenocarcinoma in vivo and in vitro

Luo

Chimge

Zhou

et al. 2018

Intl Journal of Cancer

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Claudins are a family of transmembrane proteins integral to the structure and function of tight junctions (TJ). Disruption of TJ and alterations in claudin expression are important features of invasive and metastatic cancer cells. Expression of CLDN18.1, the lung-specific isoform of CLDN18, is markedly decreased in lung adenocarcinoma (LuAd). Furthermore, we recently observed that aged Cldn18−/− mice have increased propensity to develop LuAd. We now demonstrate that CLDN18.1 expression correlates inversely with promoter methylation and with LuAd patient mortality. In addition, when restored in LuAd cells that have lost expression, CLDN18.1 markedly attenuates malignant properties including xenograft tumor growth in vivo as well as cell proliferation, migration, invasion and anchorage-independent colony formation in vitro. Based on high throughput analyses of Cldn18−/− murine lung alveolar epithelial type II cells, as well as CLDN18.1-repleted human LuAd cells, we hypothesized and subsequently confirmed by Western analysis that CLDN18.1 inhibits insulin-like growth factor-1 receptor (IGF-1R) and AKT phosphorylation. Consistent with recent data in Cldn18−/− knockout mice, expression of CLDN18.1 in human LuAd cells also decreased expression of transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP) and their target genes, contributing to its tumor suppressor activity. Moreover, analysis of LuAd cells in which YAP and/or TAZ are silenced with siRNA suggests that inhibition of TAZ, and possibly YAP, is also involved in CLDN18.1-mediated AKT inactivation. Taken together, these data indicate a tumor suppressor role for CLDN18.1 in LuAd mediated by a regulatory network that encompasses YAP/TAZ, IGF-1R and AKT signaling.

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CLDN1 induces autophagy to promote proliferation and metastasis of esophageal squamous carcinoma through AMPK/STAT1/ULK1 signaling

Gao

et al. 2019

Journal Cellular Physiology

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Tight junction is a structural constitution in cell-cell adhesion and play an important role in the maintenance of permeability and integrity of normal epithelial cell barrier.The protein encoded by Claudin 1 (CLDN1), a member of the claudin family, is an integral membrane protein and a component of tight junction strands. CLDN1 has been proved to regulate the proliferation and metastasis of multiple tumors, but little is known about its role in esophageal squamous cell carcinoma (ESCC). Here, we found that CLDN1 was aberrantly increased in ESCC tissues and cell lines, and mainly distributed in the nucleus of tumor cells. Furthermore, we confirmed that CLDN1 promoted the proliferation and metastasis of ESCC by triggering autophagy both in vitro and in vivo. Mechanically, we validated that CLDN1-induced autophagy via increasing Unc-51 like autophagy activating kinase 1 (ULK1) expression through AMP-activated protein kinase (AMPK)/signal transducer and activator of transcription 1 (STAT1) signaling pathway in ESCC cells. Taken together, our findings demonstrated that aberrant expression and distribution of CLDN1 promoted the proliferation and metastasis of esophageal squamous carcinoma by triggering autophagy through AMPK/STAT1/ULK1 signaling pathway. K E Y W O R D S AMPK/STAT1/ULK1 signaling, autophagy, CLDN1, esophageal squamous cell carcinoma, proliferation, and metastasis

show abstract

Claudin-18 inhibits cell proliferation and motility mediated by inhibition of phosphorylation of PDK1 and Akt in human lung adenocarcinoma A549 cells

Cited by 40 publications

References 41 publications

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

Claudin-18–mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis

CLDN18.1 attenuates malignancy and related signaling pathways of lung adenocarcinoma in vivo and in vitro

CLDN1 induces autophagy to promote proliferation and metastasis of esophageal squamous carcinoma through AMPK/STAT1/ULK1 signaling

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