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      Curcumin Induces Autophagy via Inhibition of Yes-Associated Protein (YAP) in Human Colon Cancer Cells

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          Abstract

          Background

          Colon cancer is one of the most common cancers and it is the fourth leading cause of cancer-related deaths worldwide. YAP can promote cell proliferation and inhibit apoptosis, leading to loss of cell contact inhibition and promoting malignant cell transformation.

          Material/Methods

          In this study we analyzed the effects of different curcumin concentrations on the proliferation of colon cancer cells using MTT and colony formation assays. Western blot detection was performed to confirm the YAP, LC3-II, and P62 expression.

          Results

          Curcumin inhibited proliferation and promoted colon cancer cell autophagy. In addition, Western blot results indicated that curcumin suppressed YAP expression in colon cancer cells. To assess the mechanism, we treated the cell lines with curcumin and assessed YAP overexpression and YAP knockdown. The results revealed that curcumin inhibits the proliferation and promotes autophagy of these cell lines. Western blot results showed that curcumin reversed the effect of YAP in colon cancer cells.

          Conclusions

          Our results suggest that YAP has great promise for treatment of colon cancer and that it might be a potential diagnostic marker for colon cancer.

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          Most cited references 16

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          Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase.

          We have identified recessive overproliferation mutations by screening and examining clones of mutant cells in genetic mosaics of the fruitfly Drosophila melanogaster. This type of screen provides a powerful approach for identifying and studying potential tumor suppressors. One of the identified genes, lats, has been cloned and encodes a putative protein kinase that shares high levels of sequence similarity with three proteins in budding yeast and Neurospora that are involved in regulation of the cell cycle and growth. Mutations in lats cause dramatic overproliferation phenotypes and various developmental defects in both mosaic animals and homozygous mutants.
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            Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance.

            Ablation of the kinases Mst1 and Mst2, orthologs of the Drosophila antiproliferative kinase Hippo, from mouse intestinal epithelium caused marked expansion of an undifferentiated stem cell compartment and loss of secretory cells throughout the small and large intestine. Although median survival of mice lacking intestinal Mst1/Mst2 is 13 wk, adenomas of the distal colon are common by this age. Diminished phosphorylation, enhanced abundance, and nuclear localization of the transcriptional coactivator Yes-associated protein 1 (Yap1) is evident in Mst1/Mst2-deficient intestinal epithelium, as is strong activation of β-catenin and Notch signaling. Although biallelic deletion of Yap1 from intestinal epithelium has little effect on intestinal development, inactivation of a single Yap1 allele reduces Yap1 polypeptide abundance to nearly wild-type levels and, despite the continued Yap hypophosphorylation and preferential nuclear localization, normalizes epithelial structure. Thus, supraphysiologic Yap polypeptide levels are necessary to drive intestinal stem cell proliferation. Yap is overexpressed in 68 of 71 human colon cancers and in at least 30 of 36 colon cancer-derived cell lines. In colon-derived cell lines where Yap is overabundant, its depletion strongly reduces β-catenin and Notch signaling and inhibits proliferation and survival. These findings demonstrate that Mst1 and Mst2 actively suppress Yap1 abundance and action in normal intestinal epithelium, an antiproliferative function that frequently is overcome in colon cancer through Yap1 polypeptide overabundance. The dispensability of Yap1 in normal intestinal homeostasis and its potent proliferative and prosurvival actions when overexpressed in colon cancer make it an attractive therapeutic target.
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              Curcumin promotes differentiation of glioma-initiating cells by inducing autophagy.

              Glioblastoma (GBM) is a highly aggressive brain tumor characterized by increased proliferation and resistance to chemotherapy and radiotherapy. Recently, a growing body of evidence suggests that glioma-initiating cells (GICs) are responsible for the initiation and recurrence of GBM. However, the factors determining the differential development of GICs remain poorly defined. In the present study, we show that curcumin, a natural compound with low toxicity in normal cells, significantly induced differentiation of GICs in vivo and in vitro by inducing autophagy. Moreover, curcumin also suppressed tumor formation on intracranial GICs implantation into mice. Our results suggest that autophagy plays an essential role in the regulation of GIC self-renewal, differentiation, and tumorigenic potential, suggesting autophagy could be a promising therapeutic target in a subset of glioblastomas. This is the first evidence that curcumin has differentiating and tumor-suppressing actions on GICs. © 2011 Japanese Cancer Association.
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                Author and article information

                Journal
                Med Sci Monit
                Med. Sci. Monit
                Medical Science Monitor
                Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
                International Scientific Literature, Inc.
                1234-1010
                1643-3750
                2018
                03 October 2018
                : 24
                : 7035-7042
                Affiliations
                [1 ]Laboratory of Cancer, College of Life Science and Bioengineering, Beijing University of Technology, Beijing, P.R. China
                [2 ]Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei, P.R. China
                [3 ]Reproductive Medicine Centre, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, P.R. China
                Author notes
                Corresponding Authors: Yinghui Huang, e-mail: yhuang@ 123456bjut.edu.en , Jing Zhu, e-mail: Jing_Zhu0719@ 123456163.com
                [A]

                Study Design

                [B]

                Data Collection

                [C]

                Statistical Analysis

                [D]

                Data Interpretation

                [E]

                Manuscript Preparation

                [F]

                Literature Search

                [G]

                Funds Collection

                Article
                910650
                10.12659/MSM.910650
                6354647
                30281585
                © Med Sci Monit, 2018

                This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International ( CC BY-NC-ND 4.0)

                Categories
                Lab/In Vitro Research

                autophagy, colonic neoplasms, curcumin

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