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      A novel derivative of betulinic acid, SYK023, suppresses lung cancer growth and malignancy

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          Abstract

          Herein, we evaluated the anti-cancer effect and molecular mechanisms of a novel betulinic acid (BA) derivative, SYK023, by using two mouse models of lung cancer driven by Kras G12D or EGFR L858R. We found that SYK023 inhibits lung tumor proliferation, without side effects in vivo or cytotoxicity in primary lung cells in vitro. SYK023 triggered endoplasmic reticulum (ER) stress. Blockage of ER stress in SYK023-treated cells inhibited SYK023-induced apoptosis. In addition, we found that the expression of cell cycle-related genes, including cyclin A2, B1, D3, CDC25a, and CDC25b decreased but, while those of p15 INK4b, p16 INK4a, and p21 CIP1 increased following SYK023 treatment. Finally, low doses of SYK023 significantly decreased lung cancer metastasis in vitro and in vivo. Expression of several genes related to cell migration, including synaptopodin, were downregulated by SYK023, thereby impairing F-actin polymerization and metastasis. Therefore, SYK023 may be a potentially therapeutic treatment for metastatic lung cancer.

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          Endoplasmic reticulum stress: cell life and death decisions.

          C. Xu (2005)
          Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response, which is aimed initially at compensating for damage but can eventually trigger cell death if ER dysfunction is severe or prolonged. The mechanisms by which ER stress leads to cell death remain enigmatic, with multiple potential participants described but little clarity about which specific death effectors dominate in particular cellular contexts. Important roles for ER-initiated cell death pathways have been recognized for several diseases, including hypoxia, ischemia/reperfusion injury, neurodegeneration, heart disease, and diabetes.
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            Targeting ER stress induced apoptosis and inflammation in cancer.

            A Garg, Patrizia Agostinis, Tom Verfaillie (2013)
            Disturbance in the folding capacity of the endoplasmic reticulum (ER), caused by a variety of endogenous and exogenous insults, prompts a cellular stress condition known as ER stress. ER stress is initially shaped to re-establish ER homeostasis through the activation of an integrated intracellular signal transduction pathway termed as unfolded protein response (UPR). However, when ER stress is too severe or prolonged, the pro-survival function of the UPR turns into a toxic signal, which is predominantly executed by mitochondrial apoptosis. Moreover, accumulating evidence implicates ER stress pathways in the activation of various 'classical' inflammatory processes in and around the tumour microenvironment. In fact, ER stress pathways evoked by certain conventional or experimental anticancer modalities have been found to promote anti-tumour immunity by enhancing immunogenicity of dying cancer cells. Thus, the ER functions as an essential sensing organelle capable of coordinating stress pathways crucially involved in maintaining the cross-talk between the cancer cell's intracellular and extracellular environment. In this review we discuss the emerging link between ER stress, cell fate decisions and immunomodulation and the potential therapeutic benefit of targeting this multifaceted signaling pathway in anticancer therapy. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
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              PKB/Akt-dependent regulation of cell motility.

              Brian A. Hemmings, Gongda Xue (2013)
              The prosurvival activity of phosphoinositide 3 kinase (PI3K)/Akt (also known as protein kinase B, PKB) pathway has been investigated in great detail in human physiology and disease. Accumulating evidence is emerging that this signaling axis also actively engages with the migratory process in motile cells, including metastatic cancer cells. Interference with the role of PI3K/Akt-mediated cell motility impairs cellular development and attenuates malignant progression of cancer metastasis. Because metastasis is responsible for 90% of mortality in cancer patients, the acceleration of cancer cell spreading observed in association with hyperactivation of the PI3K pathway, triggered for example by chemotherapy/radiotherapy in the clinic, has heightened awareness of the conflict between "good drugs" and unfavorable effects. Here, we discuss recent studies on PI3K/Akt-regulated cell motility in both physiological and pathological settings, with the aim of a better understanding of how activities of the PI3K/Akt axis initiate and transmit "migratory signals" that stimulate cell movement. We focus in particular on its direct influence on cell migration and invasion, epithelial-mesenchymal transition, and cancer metastasis.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 30 May 2015
                Publication date (Electronic): 30 March 2015
                Volume: 6
                Issue: 15
                Pages: 13671-13687
                Affiliations
                1 Center for Infection Disease and Signal Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan
                2 Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan
                3 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
                4 Department of Internal Medicine, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan
                5 Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
                6 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA
                7 Laboratory of Pharmacognosy, Graduate School of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Japan
                8 Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan
                9 Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
                10 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
                Author notes
                Correspondence to: Jan-Jong Hung, petehung@ 123456mail.ncku.edu.tw
                Wen-Chang Chang, wcchang@ 123456tmu.edu.tw
                Kuo-Hsiung Lee, khlee@ 123456unc.edu
                Article
                DOI: 10.18632/oncotarget.3701
                PMC ID: 4537041
                PubMed ID: 25909174
                SO-VID: bd894891-6d2c-4b7c-a35f-bb66fe53df34
                Copyright © Copyright: © 2015 Hsu et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 3 November 2014
                Date accepted : 2 March 2015
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: syk023,er stress,metastasis,synaptopodin
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: syk023, er stress, metastasis, synaptopodin

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