6
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Targeting FAT1 Inhibits Carcinogenesis, Induces Oxidative Stress and Enhances Cisplatin Sensitivity through Deregulation of LRP5/WNT2/GSS Signaling Axis in Oral Squamous Cell Carcinoma

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          FAT atypical cadherin 1 (FAT1) regulates cell-cell adhesion and extracellular matrix architecture, while acting as tumor suppressor or oncogene, context-dependently. Despite implication of FAT1 in several malignancies, its role in oral squamous cell carcinoma (OSCC) remains unclear. Herein, we document the driver-oncogene role of FAT1, and its mediation of cell-death evasion, proliferation, oncogenicity, and chemoresistance in OSCC. In-silica analyses indicate FAT1 mutations are frequent and drive head-neck SCC, with enhanced expression defining high-risk population and poor prognosis. We demonstrated aberrant FAT1 mRNA and protein expression in OSCC compared with non-cancer tissues, whereas loss-of-FAT1-function attenuates human primary SAS and metastatic HSC-3 OSCC cell viability, without affecting normal primary human gingival fibroblast cells. shFAT1 suppressed PCNA and upregulated BAX/BCL2 ratio in SAS and HSC-3 cells. Moreover, compared with wild-type cells, shFAT1 concomitantly impaired HSC-3 cell migration, invasion, and clonogenicity. Interestingly, while over-expressed FAT1 characterized cisplatin-resistance (CispR), shFAT1 synchronously re-sensitized CispR cells to cisplatin, enhanced glutathione (GSH)/GSH synthetase (GSS)-mediated oxidative stress and deregulated LRP5/WNT2 signaling. Concisely, FAT1 is an actionable driver-oncogene in OSCC and targeting FAT1 in patients with erstwhile cisplatin-resistant OSCC is therapeutically promising.

          Related collections

          Most cited references33

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          Role of Glutathione in Cancer Progression and Chemoresistance

          Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and disturbances in GSH homeostasis are involved in the etiology and progression of many human diseases including cancer. While GSH deficiency, or a decrease in the GSH/glutathione disulphide (GSSG) ratio, leads to an increased susceptibility to oxidative stress implicated in the progression of cancer, elevated GSH levels increase the antioxidant capacity and the resistance to oxidative stress as observed in many cancer cells. The present review highlights the role of GSH and related cytoprotective effects in the susceptibility to carcinogenesis and in the sensitivity of tumors to the cytotoxic effects of anticancer agents.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes.

            Cisplatin is one of the most effective broad-spectrum anticancer drugs. Its effectiveness seems to be due to the unique properties of cisplatin, which enters cells via multiple pathways and forms multiple different DNA-platinum adducts while initiating a cellular self-defense system by activating or silencing a variety of different genes, resulting in dramatic epigenetic and/or genetic alternations. As a result, the development of cisplatin resistance in human cancer cells in vivo and in vitro by necessity stems from bewilderingly complex genetic and epigenetic changes in gene expression and alterations in protein localization. Extensive published evidence has demonstrated that pleiotropic alterations are frequently detected during development of resistance to this toxic metal compound. Changes occur in almost every mechanism supporting cell survival, including cell growth-promoting pathways, apoptosis, developmental pathways, DNA damage repair, and endocytosis. In general, dozens of genes are affected in cisplatin-resistant cells, including pathways involved in copper metabolism as well as transcription pathways that alter the cytoskeleton, change cell surface presentation of proteins, and regulate epithelial-to-mesenchymal transition. Decreased accumulation is one of the most common features resulting in cisplatin resistance. This seems to be a consequence of numerous epigenetic and genetic changes leading to the loss of cell-surface binding sites and/or transporters for cisplatin, and decreased fluid phase endocytosis.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Glutathione metabolism in cancer progression and treatment resistance

              Bansal and Simon discuss strategies to block glutathione synthesis and utilization pathways to inhibit tumor propagation and treatment resistance.
                Bookmark

                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                27 November 2019
                December 2019
                : 11
                : 12
                : 1883
                Affiliations
                [1 ]Division of Oral and Maxillofacial Surgery, Department of Dentistry, Taipei Medical University―Shuang Ho Hospital, New Taipei City 235, Taiwan
                [2 ]School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei City 110, Taiwan
                [3 ]Department of Otolaryngology, Taitung Mackay Memorial Hospital, Taitung City 950, Taiwan
                [4 ]Department of Hematology and Oncology, Cancer Center, Taipei Medical University—Shuang Ho Hospital, New Taipei City 235, Taiwan
                [5 ]Department of Medical Research & Education, Taipei Medical University―Shuang Ho Hospital, New Taipei City 235, Taiwan
                [6 ]Graduate Institute of Clinical Medicine, School of Medicine, Taipei Medical University, Taipei City 110, Taiwan
                [7 ]Taipei Cancer Center, Taipei Medical University, Taipei City 110, Taiwan
                Author notes
                [* ]Correspondence: 16625@ 123456s.tmu.edu.tw ; Tel.: +886-2-249-0088 (ext. 8742); Fax: +886-2-2248-0900
                [†]

                These authors contribute equally to this paper.

                Author information
                https://orcid.org/0000-0001-8229-0408
                Article
                cancers-11-01883
                10.3390/cancers11121883
                6966489
                31783581
                e526cc4e-cfe9-43ea-a195-8b95a9a20d50
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 22 October 2019
                : 21 November 2019
                Categories
                Article

                oscc,squamous cell carcinoma,fat1,atypical cadherin,oncogene,chemoresistance,cisplatin,wnt signaling,lrp5,oxidative stress,gsh,gss

                Comments

                Comment on this article