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Journal of Mind and Medical Sciences Volume 7 Issue 1 Article 7 2020 The Serine/Threonine Protein Kinase (Akt)/ Protein Kinase B (PkB) Signaling Pathway in Breast Cancer Daniela Miricescu FACULTY OF DENTAL MEDICINE, DEPARTMENT OF BIOCHEMISTRY, BUCHAREST, ROMANIA Camelia Cristina Diaconu CAROL DAVILA UNIVERSITY OF MEDICINE AND PHARMACY, CLINICAL EMERGENCY HOSPITAL OF BUCHAREST, INTERNAL MEDICINE CLINIC, BUCHAREST, ROMANIA Constantin Stefani CAROL DAVILA UNIVERSITY OF MEDICINE AND PHARMACY, DEPARTMENT OF FAMILY MEDICINE, BUCHAREST, ROMANIA Ana Maria Alexandra Stanescu CAROL DAVILA UNIVERSITY OF MEDICINE AND PHARMACY, DEPARTMENT OF FAMILY MEDICINE, BUCHAREST, ROMANIA Alexandra Totan FAollowCULT thisY OF and DEN additionalTAL MEDICINE, works at:DEP https:/ARTMEN/scholarT OF.v BIOCHEMISTRalpo.edu/jmmsY, BUCHAREST, ROMANIA Part of the Obstetrics and Gynecology Commons, Oncology Commons, and the Palliative Care SeeCommons next page for additional authors Recommended Citation Miricescu, Daniela; Diaconu, Camelia Cristina; Stefani, Constantin; Stanescu, Ana Maria Alexandra; Totan, Alexandra; Rusu, Ioana Ruxandra; Bratu, Ovidiu Gabriel; Spinu, Dan; and Greabu, Maria (2020) "The Serine/ Threonine Protein Kinase (Akt)/ Protein Kinase B (PkB) Signaling Pathway in Breast Cancer," Journal of Mind and Medical Sciences: Vol. 7 : Iss. 1 , Article 7. DOI: 10.22543/7674.71.P3439 Available at: https://scholar.valpo.edu/jmms/vol7/iss1/7 This Review Article is brought to you for free and open access by ValpoScholar. It has been accepted for inclusion in Journal of Mind and Medical Sciences by an authorized administrator of ValpoScholar. For more information, please contact a ValpoScholar staff member at [email protected]. The Serine/Threonine Protein Kinase (Akt)/ Protein Kinase B (PkB) Signaling Pathway in Breast Cancer Authors Daniela Miricescu, Camelia Cristina Diaconu, Constantin Stefani, Ana Maria Alexandra Stanescu, Alexandra Totan, Ioana Ruxandra Rusu, Ovidiu Gabriel Bratu, Dan Spinu, and Maria Greabu This review article is available in Journal of Mind and Medical Sciences: https://scholar.valpo.edu/jmms/vol7/iss1/7 Journal of Mind and Medical Sciences https://scholar.valpo.edu/jmms/ https://proscholar.org/jmms/ I S S N : 2 3 9 2 - 7 6 7 4 The Serine/Threonine Protein Kinase (Akt)/ Protein Kinase B (PkB) Signaling Pathway in Breast Cancer Daniela Miricescu1, Camelia Cristina Diaconu2, Constantin Stefani3,4, Ana Maria Alexandra Stanescu3, Alexandra Totan1, Ioana Ruxandra Rusu5, Ovidiu Gabriel Bratu4, Dan Spinu4, Maria Greabu1 1 FACULTY OF DENTAL MEDICINE, DEPARTMENT OF BIOCHEMISTRY, BUCHAREST, ROMANIA 2 CAROL DAVILA UNIVERSITY OF MEDICINE AND PHARMACY, CLINICAL EMERGENCY HOSPITAL OF BUCHAREST, INTERNAL MEDICINE CLINIC, BUCHAREST, ROMANIA 3 CAROL DAVILA UNIVERSITY OF MEDICINE AND PHARMACY, DEPARTMENT OF FAMILY MEDICINE, BUCHAREST, ROMANIA 4 CAROL DAVILA UNIVERSITY CENTRAL EMERGENCY MILITARY HOSPITAL, BUCHAREST, ROMANIA 5 CAROL DAVILA UNIVERSITY OF MEDICINE AND PHARMACY, FACULTY OF MEDICINE, DEPARTMENT OF ANATOMY AND EMBRYOLOGY, BUCHAREST, ROMANIA ABSTRACT ARTICLE DATA According to statistical data published in 2019, breast cancer is among the leading causes of death in women worldwide. The serine/threonine kinase Category: Review (AKT) or protein kinase B (PkB) signaling pathway is activated by Received: January 09, 2020 phosphorylation processes, which further is associated with cell growth, Accepted: February 18, 2020 proliferation, and survival, but also with activation of glucose metabolism. Mutations of the AKT signaling pathway components (especially PI3KCA Keywords: and PTEN) have been observed in breast cancer patients, which are Protein Kinase, Breast Cancer, Mutation. associated with resistance to hormonal treatment. Many clinical trials are testing the effect of AKT inhibition in order to block the growth and *Corresponding author: proliferation of breast cancer cells. The purpose of this review is to present Camelia Diaconu, Clinical Emergency Hospital of the incidence of this neoplastic disease, to describe AKT signaling Bucharest, Internal Medicine Clinic, Calea Floreasca No. 8, Bucharest, Romania, pathways activation, mutations that occur at its level, and inhibitors that E-mail: [email protected] can block this protein kinase. Introduction 2018, 38,439 cases of cancer were diagnosed in women, of which 9625 were breast cancer [2]. Last year, Romania Following a systemic analysis conducted over a period registered 30,100 deaths among men and 20,200 among of 27 years (1990-2017) regarding the incidence of women. In the case of women of Romanian origin, as well cancer, published online in September 2019, there were as in other countries, breast cancer represents the most 24.5 million cases and 9.6 million deaths registered common neoplastic disease, with 8,981 cases reported. worldwide [1]. Skin, breast, and colorectal cancer were Breast palpation and clinical breast examination are the most common neoplastic disorders reported among the classic methods available to all women for detecting women, representing 54% of all cancers [1]. In the Global tumors, as mammography is not generally available at the top 10 cancers, breast cancer was the third most common public health care level in many areas [3]. cancer overall, with 2 million incident cases registered in 2017. Of the 143 countries that participated in the Discussions systemic analysis, in 112 countries breast cancer was the most common cause of death among women [1]. Breast cancer subtypes According to statistical data from Romania, the Currently, for a more accurate diagnosis of breast incidence of neoplastic diseases in 2018 registered at cancer, a number of factors have been proposed, such as 83,461 cases for both sexes, with 50,902 deaths [2]. In tumor size and degree, histological subtype, Romanian women, the 5 most common types of cancer are lymphovascular invasion of tumor cells, presence of breast, colorectal, cervix uteri, lung, and corpus uteri. In tumor cell receptors, and axial lymph nodes. To cite this article: Daniela Miricescu, Camelia Cristina Diaconu, Constantin Stefani, Ana Maria Alexandra Stanescu, Alexandra Totan, Ioana Ruxandra Rusu, Ovidiu Gabriel Bratu, Dan Spinu, Maria Greabu. The Serine/Threonine Protein Kinase (Akt)/ Protein Kinase B (PkB) Signaling Pathway in Breast Cancer. J Mind Med Sci. 2020; 7(1):34-39. DOI: 10.22543/7674.71.P3439 Camelia C. Diaconu et al. Ki-67 is currently used as a valuable parameter that catalytic subunit phosphorylates phosphatidylinositol 4,5 expresses the potential for proliferation and division of bisphosphate (PIP2) to phosphatidyl inositol 3,4,5 tumor cells. By combining genetic tests with histological triphosphate (PIP3). PIP3 acts as a secondary messenger analyses (macroscopic and microscopic) and and coordinates AKT localization at the plasma membrane immunohistochemistry, it is possible to detect the presence and then phosphorylation by PDK1 (phosphoinositide of cell surface receptors [estrogen, progesterone, and dependent protein kinase-1) [10]. PDK1 phosphorylates human epidermal growth factor receptor 2 (HER2)] [4]. AKT at threonine residue 308, and for complete activation, Luminal A, Luminal B with HER 2 negative, Luminal serine residue 473 is phosphorylated by mTOR B with Her 2 positive, HER 2 enriched, and basal-like (mammalian target of rapamycin) [10,11]. (triple negative) are the most recent classifications (in mTOR is a serine / threonine protein kinase complex 2013) for breast cancer, according to the St Gallen that is composed of mTORC 1 and mTORC 2, these classification system (Table 1) [4]. having similar structure but different functions. mTORC2 Table 1. According to St. Gallen classification [adapted phosphorylates AKT for full activation at serine. from 4-7] Following activation by phosphorylation of AKT, this protein kinase phosphorylates and thus inhibits tuberous Breast ER / Pr HER 2 Ki67 Mutated genes Treatment cancer sclerosis complex 1 and 2 (TSC 1 and 2), this inhibition subtypes leading to the activation of mTORC1. Once activated Luminal A +and or/- - <14% PIK3CA(45%) Endocrine mTORC1, it activates in turn 40 S ribosomal protein S6 AKT1(4%) therapy PTEN(4%) kinase (S6K) and eukaryotic initiation factor 4E binding Luminal B + and - ≥14% PIK3CA (29%) Endocrine protein (4EBP1) which lead to cell growth and activation and HER or/- therapy± of glucose metabolism [12,13]. negative chemotherapy Phosphatase and tensin homolog (PTEN) negatively Luminal B + and + Any PIK3CA (29%) Chemotherapy and HER or/- ki-67 + anti+HER2 regulate AKT by dephosphorylating PIP3 to PIP2. Apart positive therapy+endoc from PTEN, it has recently been observed that there may rine therapy HER-2- -/- + Any PIK3CA (39%) Chemotherapy be another negative regulator for PIP3, polyphosphate 4- enriched ki-67 + anti+HER 2 phosphatase type II (INPP4B) [14]. Basal-like -/- - - PIK3CA (7%) Chemotherapy (triple AKT activation in cancer negative) The incidence of mutations that occur in the AKT Pi3k signaling pathway signaling pathway in breast cancer is 25%. Most of these Phosphatidylinositol-3 kinases (PI3K) are a family of mutations are found in the PIKCA that encodes the p110α lipid structure kinases involved in the regulation of catalytic subunit, with the substitution of a single amino numerous biological processes, such as cell proliferation, acid such as E545K and E542K in the helical domain survival and differentiation, metabolism, and migration (exon 9) and H1047R in the kinase domain (exon20) [15]. [8]. Depending
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    Supplementary Table 1. In vitro side effect profiling study for LDN/OSU-0212320. Percent Inhibition Receptor 10 µM Neurotransmitter Related Adenosine, Non-selective 7.29% Adrenergic, Alpha 1, Non-selective 24.98% Adrenergic, Alpha 2, Non-selective 27.18% Adrenergic, Beta, Non-selective -20.94% Dopamine Transporter 8.69% Dopamine, D1 (h) 8.48% Dopamine, D2s (h) 4.06% GABA A, Agonist Site -16.15% GABA A, BDZ, alpha 1 site 12.73% GABA-B 13.60% Glutamate, AMPA Site (Ionotropic) 12.06% Glutamate, Kainate Site (Ionotropic) -1.03% Glutamate, NMDA Agonist Site (Ionotropic) 0.12% Glutamate, NMDA, Glycine (Stry-insens Site) 9.84% (Ionotropic) Glycine, Strychnine-sensitive 0.99% Histamine, H1 -5.54% Histamine, H2 16.54% Histamine, H3 4.80% Melatonin, Non-selective -5.54% Muscarinic, M1 (hr) -1.88% Muscarinic, M2 (h) 0.82% Muscarinic, Non-selective, Central 29.04% Muscarinic, Non-selective, Peripheral 0.29% Nicotinic, Neuronal (-BnTx insensitive) 7.85% Norepinephrine Transporter 2.87% Opioid, Non-selective -0.09% Opioid, Orphanin, ORL1 (h) 11.55% Serotonin Transporter -3.02% Serotonin, Non-selective 26.33% Sigma, Non-Selective 10.19% Steroids Estrogen 11.16% 1 Percent Inhibition Receptor 10 µM Testosterone (cytosolic) (h) 12.50% Ion Channels Calcium Channel, Type L (Dihydropyridine Site) 43.18% Calcium Channel, Type N 4.15% Potassium Channel, ATP-Sensitive -4.05% Potassium Channel, Ca2+ Act., VI 17.80% Potassium Channel, I(Kr) (hERG) (h) -6.44% Sodium, Site 2 -0.39% Second Messengers Nitric Oxide, NOS (Neuronal-Binding) -17.09% Prostaglandins Leukotriene,
  • Inhibition of Spinach Phosphoribulokinase by DL-Glyceraldehyde by ANTONI R

    Inhibition of Spinach Phosphoribulokinase by DL-Glyceraldehyde by ANTONI R

    Biochem. J. (1976) 153, 613-619 613 Printed in Great Britain Inhibition of Spinach Phosphoribulokinase by DL-Glyceraldehyde By ANTONI R. SLABAS and DAVID A. WALKER Department ofBotany, University ofSheffield, Sheffield S1O 2TN, U.K. (Received 10 September 1975) Spinach chloroplast phosphoribulokinase is inhibited by DL-glyceraldehyde. The in- hibition is non-competitive with respect to ribulose 5-phosphate (Ki 19mM) and ATP (Ki 20mM). The inhibition is discussed in relation to a previously reported inhibition of CO2 assimilation in intact and envelope-free chloroplasts by DL-glyceraldehyde. It is concluded that the inhibition of phosphoribulokinase is insufficient to account for the inhibition, by DL-glyceraldehyde, of 02 evolution with ribose 5-phosphate as substrate and that a further site of inhibition is also present in this system. DL-Glyceraldehyde inhibits photosynthetic carbon glycylglycine buffer, pH7.4, in a total volume of assiniilation by intact chloroplasts and by the re- 13 ml. The reaction was terminated by the addition constituted chloroplast system (Stokes & Walker, of 2ml of 50 % (w/v) trichloroacetic acid and the pH 1972). The inhibition is most pronounced with intact was adjusted to pH8.0 with KOH. After the addition chloroplasts, a concentration of 1OmM being sufficient of Sml of 1.OM-barium acetate the solution was to suppress 02 evolution completely. It is important centrifuged and the precipitate discarded after because DL-glyceraldehyde is the only known inhibi- washing with Sml of water. Cold ethanol (4vol.) was tor of photosynthesis that is entirely without detect- added to the combined supernatants (total volume able effect on photophosphorylation or photo- 25.4ml); the new precipitate was recovered by synthetic electron transport.