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      Expression of the β3 subunit of Na +/K +-ATPase is increased in gastric cancer and regulates gastric cancer cell progression and prognosis via the PI3/AKT pathway

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          Abstract

          ATP1B3 encodes the β3 subunit of Na +/K +-ATPase and is located in the q22-23 region of chromosome 3. Na +/K +-ATPase participates in normal cellular activities but also plays a crucial role in carcinogenesis. In the present study, we found that expression of the β3 subunit of Na +/K +-ATPase was increased in human gastric cancer tissues compared with that in normal matched tissues and that this increased expression predicted a poor outcome. ATP1B3 expression was elevated at both the mRNA and protein levels in gastric cancer cell lines relative to those in a normal gastric epithelial cell line. Interestingly, ATP1B3 knockdown significantly inhibited cell proliferation, colony-formation ability, migration, and invasion and increased apoptosis in human gastric carcinoma cell lines. Additionally, knockdown induced cell cycle arrest at the G2/M phase. Furthermore, we demonstrated that ATP1B3 silencing decreased the expression of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT) and phosphorylated AKT (p-AKT), indicating that ATP1B3 regulates gastric cancer cell progression via the PI3K/AKT signalling pathway. Hence, the β3 subunit of Na +/K +-ATPase plays an essential role in the tumourigenesis of gastric cancer and may be a potential prognostic and therapeutic target for the treatment of gastric cancer.

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          AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation.

          S Rittenhouse, Andrew T. Chan, Philip N. Tsichlis (1998)
          The protein kinase Akt/PKB is activated via a multistep process by a variety of signals. In the early steps of this process, PI-3 kinase-generated D3-phosphorylated phosphoinositides bind the Akt PH domain and induce the translocation of the kinase to the plasma membrane where it co-localizes with phosphoinositide-dependent kinase-1. By binding to the PH domains of both Akt and phosphoinositide-dependent kinase-1, D3-phosphorylated phosphoinositides appear to also induce conformational changes that permit phosphoinositide-dependent kinase-1 to phosphorylate the activation loop of Akt. The paradigm of Akt activation via phosphoinositide-dependent phosphorylation provided a framework for research into the mechanism of activation of other members of the AGC kinase group (p70S6K, PKC, and PKA) and members of the Tec tyrosine kinase family (TecI, TecII, Btk/Atk, Itk/Tsk/Emt, Txk/Rlk, and Bm/Etk). The result was the discovery that these kinases and Akt are activated by overlapping pathways. In this review, we present our current understanding of the regulation and function of the Akt kinase and we discuss the common and unique features of the activation processes of Akt and the AGC and Tec kinase families. In addition, we present an overview of the biosynthesis of phosphoinositides that contribute to the regulation of these kinases.
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            Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway.

            Dong-Mei Zhang, Jun-Shan Liu, Li-Juan Deng … (2013)
            Hepatocellular carcinoma (HCC) is a deadly form of cancer without effective chemotherapy so far. Currently, only sorafenib, a multitargeted tyrosine kinase inhibitor, slightly improves survival in HCC patients. In searching for natural anti-HCC components from toad venom, which is frequently used in the treatment of liver cancer in traditional Chinese medicine, we discovered that arenobufagin, a bufadienolide from toad venom, had potent antineoplastic activity against HCC HepG2 cells as well as corresponding multidrug-resistant HepG2/ADM cells. We found that arenobufagin induced mitochondria-mediated apoptosis in HCC cells, with decreasing mitochondrial potential, as well as increasing Bax/Bcl-2 expression ratio, Bax translocation from cytosol to mitochondria. Arenobufagin also induced autophagy in HepG2/ADM cells. Autophagy-specific inhibitors (3-methyladenine, chloroquine and bafilomycin A1) or Beclin1 and Atg 5 small interfering RNAs (siRNAs) enhanced arenobufagin-induced apoptosis, indicating that arenobufagin-mediated autophagy may protect HepG2/ADM cells from undergoing apoptotic cell death. In addition, we observed the inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway by arenobufagin. Interestingly, inhibition of mTOR by rapamycin or siRNA duplexes augmented arenobufagin-induced apoptosis and autophagy. Finally, arenobufagin inhibited the growth of HepG2/ADM xenograft tumors, which were associated with poly (ADP-ribose) polymerase cleavage, light chain 3-II activation and mTOR inhibition. In summary, we first demonstrated the antineoplastic effect of arenobufagin on HCC cells both in vitro and in vivo. We elucidated the underlying antineoplastic mechanisms of arenobufagin that involve cross talk between apoptosis and autophagy via inhibition of the PI3K/Akt/mTOR pathway. This study may provide a rationale for future clinical application using arenobufagin as a chemotherapeutic agent for HCC.
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              Targeting the PI3K signaling pathway in cancer therapy.

              Uriel A. Angulo-Zamudio, Chandra Bartholomeusz (2011)
              The PI3K signaling pathway is involved in the regulation of cancer cell growth, motility, survival and metabolism. The pathway is frequently active in many different types of cancer-e.g., breast, bladder, prostate, thyroid, ovarian and NSCLC. Targetable genetic aberrations in this pathway give us many opportunities for development of targeted therapies for different types of cancer. The genetic alterations in the PI3K/mammalian target of rapamycin (mTOR)/Akt pathway, as well as the drugs that target this pathway, either alone, in combination with other targeted agents or in chemotherapy. Targeted inhibitors of the PI3K pathway currently being tested in clinical trials in different types of human cancer. Small-molecule inhibitors targeting the PI3K/Akt/mTOR pathway show some success with these agents in current clinical trials. For further improvement in response, molecular correlates that can be used for patient selection, need to be determined. A more efficient and effective way to screen for patients to determine which patients are most likely to benefit from PI3K pathway inhibitors is also needed.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 13 October 2017
                Publication date (Electronic): 15 September 2017
                Volume: 8
                Issue: 48
                Pages: 84285-84299
                Affiliations
                1 Department of Gastroenterology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
                2 Department of Gastroenterology, Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
                3 Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, P.R. China
                Author notes
                Correspondence to: Jiang Cao, zimu05067@ 123456163.com
                Article
                Publisher ID: 20894
                DOI: 10.18632/oncotarget.20894
                PMC ID: 5663595
                PubMed ID: 29137423
                SO-VID: b13f7c35-5364-40e6-ae4c-4dbf7246b1cc
                Copyright © Copyright: © 2017 Li et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 9 February 2017
                Date accepted : 26 August 2017
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: atp1b3,proliferation,apoptosis,migration,gastric cancer
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: atp1b3, proliferation, apoptosis, migration, gastric cancer

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