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Calotropin activates YAP through downregulation of LATS1 in colorectal cancer cells.

ABSTRACT: Objectives: Calotropin (CTP), a natural product isolated from Calotropis gigantea, has been identified as a potential anticancer agent. In this study, we aimed to investigate the effect CTP on colorectal cancer and the role of Yes-associated protein (YAP) in CTP-inhibited cell proliferation. Methods: Cell viability and cell proliferation were detected by MTT and BrdU assay. Western blotting and immunofluorescence were performed to determine CTP-induced YAP dephosphorylation and nuclear localization. Western blotting, siRNA transfection and RT-PCR analysis were carried out to investigate the mechanisms of CTP-mediated YAP activation. The anti-tumor activities of CTP were observed in mice tumor models. Results: We demonstrated that CTP inhibits the proliferation of colorectal cancer cells both in vitro and in vivo. Moreover, we showed that CTP activates YAP in colorectal cancer cells. Mechanistically, CTP promotes LATS1 degradation via the ubiquitination/proteasome pathway, resulting in YAP dephosphorylation and nuclear localization, leading to induce YAP target genes expression in colorectal cancer cells. Inhibition of YAP activity enhances CTP-mediated inhibition of cell proliferation, suggesting that YAP plays a protective role in CTP-induced antiproliferative effect. Conclusion: Our results demonstrate that CTP markedly inhibits tumor growth and activates a protective role of YAP in colorectal cancer cells, indicating that combination of CTP and YAP targeting drugs may be a promising strategy for colorectal cancer treatment.

SUBMITTER: Zhou L

PROVIDER: S-EPMC6536122 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Calotropin activates YAP through downregulation of LATS1 in colorectal cancer cells.

Zhou Limin L Cai Luliang L Guo Yanzi Y Zhang Huanyu H Wang Peng P Yi Guohui G Huang Yonghao Y

OncoTargets and therapy 20190523

Objectives: Calotropin (CTP), a natural product isolated from Calotropis gigantea, has been identified as a potential anticancer agent. In this study, we aimed to investigate the effect CTP on colorectal cancer and the role of Yes-associated protein (YAP) in CTP-inhibited cell proliferation. Methods: Cell viability and cell proliferation were detected by MTT and BrdU assay. Western blotting and immunofluorescence were performed to determine CTP-induced YAP dephosphorylation ...[more]

PMID: 31190898

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Project description:Yes-associated protein (YAP), as a major downstream effector in the Hippo signaling pathway, is considered as an oncogene in cancer. The present study aimed to investigate the potential role of YAP in the development and progression of colorectal cancer (CRC). The mRNA and protein expression levels of YAP in human CRC tissue samples and adjacent normal tissue were analyzed using public databases, as well as clinical samples. The potential roles of YAP and the underlying mechanism regulating the proliferation and migration of CRC cells were examined using genetic manipulation in vitro. The correlation between the expression of the YAP gene and epithelial-to-mesenchymal transition (EMT) markers was investigated in order to determine the mechanism underlying the observed effects of YAP. YAP mRNA expression levels were significantly upregulated in CRC tissue compared with in normal tissue, as determined using datasets obtained from Oncomine. Similarly, in clinical samples, the protein expression levels of YAP were significantly upregulated in CRC tissue samples compared with in normal tissue samples. YAP knockdown inhibited the proliferation and migration of CRC cells in vitro, whereas its overexpression resulted in the opposite effect. The expression levels of the YAP gene were positively correlated with those of EMT markers (such as vimentin and N-cadherin) and EMT-inducing transcription factors (such as Snail1, Slug and zinc finger E-box binding homeobox 1 and 2) in CRC samples from Gene Expression Profiling Interactive Analysis. Furthermore, YAP silencing increased the protein expression of E-cadherin and decreased that of vimentin in CRC cells. By contrast, the overexpression of YAP had the opposite effect. YAP promoted the glucose transporter 3 (Glut3)/AMP-activated protein kinase (AMPK) signaling pathway in CRC cells. In conclusion, YAP promoted the proliferation and migration of CRC cells, as well as the expression of EMT markers, possibly by regulating the Glut3/AMPK signaling pathway.

Dataset Information

Calotropin activates YAP through downregulation of LATS1 in colorectal cancer cells.

Publications

Calotropin activates YAP through downregulation of LATS1 in colorectal cancer cells.

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