title: Sigma 1 Receptor antagonist potentiates the anti-cancer effect of p53 by regulating ER stress, ROS production, Bax levels, and caspase-3 activation.
abstract: Over the last years, many improvements have been made in the treatment of breast cancer; however, novel and less toxic therapies are still needed, especially for relapsing and chemo-resistant patients. Here, we analyzed the therapeutic potential of p53 and Rimcazole, a Sigma 1 Receptor antagonist. Rimcazole and p53 are being evaluated in preclinical and clinical trials, respectively. While p53 is a promising antitumor therapeutic agent, antagonists of Sigma 1 Receptor also inhibit tumor cell survival and induce apoptosis. Our current study demonstrates for the first time the synergistic effect of p53 in combination with the Sigma 1 Receptor antagonist Rimcazole. Furthermore, we show that shRNA knockdown of Sigma 1 Receptor in combination with p53, lead to a similar synergistic effect, and that this synergistic effect, in breast cancer growth suppression occurs independent of p53 status. Furthermore, this combination treatment induced ER stress, p38 MAPK activation, ROS production, and proteins involved in apoptosis (caspases-3, Bax) in breast cancer cells. Combining these therapeutic anti-cancer molecules provides an innovative approach for potentially treating human breast cancer.
authors.affiliation: Department of Biological Sciences Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, United States.
authors.forename: Mireille
authors.initials: M
authors.lastname: Happy
authors.affiliation: Department of Biological Sciences Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, United States.
authors.forename: Jordan
authors.initials: J
authors.lastname: Dejoie
authors.affiliation: Department of Biological Sciences Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, United States.
authors.forename: Cynthia K
authors.initials: CK
authors.lastname: Zajac
authors.affiliation: Department of Biological Sciences Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, United States.
authors.forename: Briseida
authors.initials: B
authors.lastname: Cortez
authors.affiliation: Department of Biological Sciences Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, United States.
authors.forename: Karabi
authors.initials: K
authors.lastname: Chakraborty
authors.affiliation: Department of Biological Sciences Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Aderemi
authors.affiliation: Department of Biological Sciences Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, United States. Electronic address: moira.sauane@Lehman.cuny.edu.
authors.forename: Moira
authors.initials: M
authors.lastname: Sauane
mesh_terms: D000256:Adenoviridae; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000628:therapy*; D002227:Carbazoles / Q000627:therapeutic use*; D053148:Caspase 3 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D012342:RNA, Small Nuclear / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D053148:Caspase 3; D012342:RNA, Small Nuclear; D017382:Reactive Oxygen Species; D017480:Receptors, sigma; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D000097605:Sigma-1 Receptor; C034931:rimcazole
keywords: Apoptosis; ER stress; ROS; Sigma 1 Receptor; p38 MAPK; p53