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      ALDH-Dependent Glycolytic Activation Mediates Stemness and Paclitaxel Resistance in Patient-Derived Spheroid Models of Uterine Endometrial Cancer

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          Summary

          Uterine endometrial cancer is associated with poor survival outcomes in patients with advanced-stage disease. Here, we developed a three-dimensional cell cultivation method of endometrioid cancer stem-like cells with high aldehyde dehydrogenase (ALDH) activity from clinical specimens. ALDH inhibition synergized with paclitaxel to block cancer proliferation. In the clinical setting, high ALDH1A1 expression was associated with poor survival. A high level of ALDH correlated with an increase of glucose uptake, activation of the glycolytic pathway, and elevation of glucose transporter 1 (GLUT1). Blockade of GLUT1 inhibited characteristics of cancer stem cells. Similarly to ALDH inhibition, GLUT1 inhibition synergized with paclitaxel to block endometrial cancer proliferation. Our data indicated that ALDH-dependent GLUT1 activation and the resulting glycolytic activation are of clinical importance for both prognostic evaluation and therapeutic decision-making in endometrial cancer patients. In addition, the synergistic effects of taxane compounds and ALDH or GLUT1 inhibitors may serve as a new clinical treatment option for endometrial cancer.

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          Highlights

          • •

            Establishment of patient-derived endometrial cancer stem cells with ALDH activity

          • •

            Endometrial cancer stemness depends on ALDH-mediated glycolysis via GLUT1

          • •

            High ALDH and GLUT expression is associated with poor outcome in endometrial cancer

          • •

            Paclitaxel and ALDH or GLUT inhibitor synergistically suppress endometrial cancer

          Abstract

          In this article, Ishiguro and colleagues demonstrated the stable in vitro cultivation of human endometrial cancer stem cells from clinical specimens. Investigation of patient-derived spheroid cells showed that ALDH-mediated glycolysis through GLUT1 was essential for endometrial cancer stem cells. ALDH and GLUT are novel therapeutic targets in endometrial cancer to complement standard taxane treatment.

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          Targeting cellular metabolism to improve cancer therapeutics

          Y. Zhao, E B Butler, Tricia Tan (2013)
          The metabolic properties of cancer cells diverge significantly from those of normal cells. Energy production in cancer cells is abnormally dependent on aerobic glycolysis. In addition to the dependency on glycolysis, cancer cells have other atypical metabolic characteristics such as increased fatty acid synthesis and increased rates of glutamine metabolism. Emerging evidence shows that many features characteristic to cancer cells, such as dysregulated Warburg-like glucose metabolism, fatty acid synthesis and glutaminolysis are linked to therapeutic resistance in cancer treatment. Therefore, targeting cellular metabolism may improve the response to cancer therapeutics and the combination of chemotherapeutic drugs with cellular metabolism inhibitors may represent a promising strategy to overcome drug resistance in cancer therapy. Recently, several review articles have summarized the anticancer targets in the metabolic pathways and metabolic inhibitor-induced cell death pathways, however, the dysregulated metabolism in therapeutic resistance, which is a highly clinical relevant area in cancer metabolism research, has not been specifically addressed. From this unique angle, this review article will discuss the relationship between dysregulated cellular metabolism and cancer drug resistance and how targeting of metabolic enzymes, such as glucose transporters, hexokinase, pyruvate kinase M2, lactate dehydrogenase A, pyruvate dehydrogenase kinase, fatty acid synthase and glutaminase can enhance the efficacy of common therapeutic agents or overcome resistance to chemotherapy or radiotherapy.
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            Cancer stem cell definitions and terminology: the devil is in the details.

            Peter Valent, Dominique Bonnet, Ruggero De Maria … (2012)
            The cancer stem cell (CSC) concept has important therapeutic implications, but its investigation has been hampered both by a lack of consistency in the terms used for these cells and by how they are defined. Evidence of their heterogeneous origins, frequencies and their genomic, as well as their phenotypic and functional, properties has added to the confusion and has fuelled new ideas and controversies. Participants in The Year 2011 Working Conference on CSCs met to review these issues and to propose a conceptual and practical framework for CSC terminology. More precise reporting of the parameters that are used to identify CSCs and to attribute responses to them is also recommended as key to accelerating an understanding of their biology and developing more effective methods for their eradication in patients.
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              Aldehyde dehydrogenase 1A1 in stem cells and cancer

              Hiroyuki Tomita, Kaori Tanaka, Takuji Tanaka … (2016)
              The human genome contains 19 putatively functional aldehyde dehydrogenase (ALDH) genes, which encode enzymes critical for detoxification of endogenous and exogenous aldehyde substrates through NAD(P)+-dependent oxidation. ALDH1 has three main isotypes, ALDH1A1, ALDH1A2, and ALDH1A3, and is a marker of normal tissue stem cells (SC) and cancer stem cells (CSC), where it is involved in self-renewal, differentiation and self-protection. Experiments with murine and human cells indicate that ALDH1 activity, predominantly attributed to isotype ALDH1A1, is tissue- and cancer-specific. High ALDH1 activity and ALDH1A1 overexpression are associated with poor cancer prognosis, though high ALDH1 and ALDH1A1 levels do not always correlate with highly malignant phenotypes and poor clinical outcome. In cancer therapy, ALDH1A1 provides a useful therapeutic CSC target in tissue types that normally do not express high levels of ALDH1A1, including breast, lung, esophagus, colon and stomach. Here we review the functions and mechanisms of ALDH1A1, the key ALDH isozyme linked to SC populations and an important contributor to CSC function in cancers, and we outline its potential in future anticancer strategies.
              Article 0 comments Cited 248 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Tatsuya Ishiguro
                Takayuki Enomoto
                Journal
                Journal ID (nlm-ta): Stem Cell Reports
                Journal ID (iso-abbrev): Stem Cell Reports
                Title: Stem Cell Reports
                Publisher: Elsevier
                ISSN (Electronic): 2213-6711
                Publication date PMC-release: 26 September 2019
                Publication date Collection: 08 October 2019
                Publication date (Electronic): 26 September 2019
                Volume: 13
                Issue: 4
                Pages: 730-746
                Affiliations
                [1 ]Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata, Niigata 951-8510, Japan
                [2 ]Division of Cancer Differentiation, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
                [3 ]Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata, Niigata 951-8510, Japan
                Author notes
                [∗ ]Corresponding author tishigur@ 123456med.niigata-u.ac.jp
                [∗∗ ]Corresponding author enomoto@ 123456med.niigata-u.ac.jp
                Article
                Publisher ID: S2213-6711(19)30309-1
                DOI: 10.1016/j.stemcr.2019.08.015
                PMC ID: 6829754
                PubMed ID: 31564647
                SO-VID: 09ca7fb5-0876-4f42-b48f-7d3ce0b7de3f
                Copyright © © 2019 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 14 January 2019
                Date revision received : 28 August 2019
                Date accepted : 29 August 2019
                Categories
                Subject: Article

                Keywords: endometrial cancer,cancer stem cells,in vitro cultivation,patient-derived xenograft tumor,aldehyde dehydrogenase,paclitaxel,drug resistance,glycolysis,glucose transporter,glut1
                Data availability:
                Keywords: endometrial cancer, cancer stem cells, in vitro cultivation, patient-derived xenograft tumor, aldehyde dehydrogenase, paclitaxel, drug resistance, glycolysis, glucose transporter, glut1

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