Ramesh B Batchu1, Oksana V Gruzdyn2, Aamer M Qazi2, Jaskiran Kaur3, Ebrahem M Mahmud3, Donald W Weaver3, Scott A Gruber2. 1. Wayne State University School of Medicine, Detroit, MI; John D. Dingell VA Medical Center, Detroit, MI; Virocan Therapeutics Pvt. Ltd, Guntur, India. Electronic address: rbatchu@med.wayne.edu. 2. Wayne State University School of Medicine, Detroit, MI; John D. Dingell VA Medical Center, Detroit, MI. 3. Wayne State University School of Medicine, Detroit, MI.
Abstract
PURPOSE: MicroRNA (miR)-26a has been identified as a tumor suppressor in pancreatic cancer cells. Although wild-type p53 controls cell-cycle progression, its mutant form normally present in pancreatic cancer loses this capability. Phosphorylation is known to restore wild-type activity to mutant p53. We, therefore, examined whether miR-26a treatment can restore wild-type functions of mutant p53 via phosphorylation, resulting in inhibition of cell growth. METHODS: The human pancreatic cancer cell line BxPc-3 harboring mutant p53 was used for colony formation, cell-cycle, and Western blotting assays. Gene profile analysis was conducted after transfection with pre-miR-26a. RESULTS: miR-26a expression significantly decreased cell proliferation by 80% along with marked inhibition of colony formation and cell migration. Cell-cycle inhibition at the G0/G1 interface was observed along with enhanced drug retention and increased chemosensitivity to gemcitabine. Mutant p53 was phosphorylated rapidly at its Ser9 and Ser392 residues, but not at Ser15 or Ser20. Gene profile analysis of pre-miR-26a-transfected cells showed a significant increase in gene transcripts promoting apoptosis and p53 activation, with decreased levels of genes involved in cell-cycle progression. CONCLUSION: Delivery of miR-26a may represent a novel strategy for inhibiting pancreatic cancer growth, at least in part by enhancing phosphorylation of mutant p53 to restore its wild-type functions.
PURPOSE:MicroRNA (miR)-26a has been identified as a tumor suppressor in pancreatic cancer cells. Although wild-type p53 controls cell-cycle progression, its mutant form normally present in pancreatic cancer loses this capability. Phosphorylation is known to restore wild-type activity to mutant p53. We, therefore, examined whether miR-26a treatment can restore wild-type functions of mutant p53 via phosphorylation, resulting in inhibition of cell growth. METHODS: The humanpancreatic cancer cell line BxPc-3 harboring mutant p53 was used for colony formation, cell-cycle, and Western blotting assays. Gene profile analysis was conducted after transfection with pre-miR-26a. RESULTS:miR-26a expression significantly decreased cell proliferation by 80% along with marked inhibition of colony formation and cell migration. Cell-cycle inhibition at the G0/G1 interface was observed along with enhanced drug retention and increased chemosensitivity to gemcitabine. Mutant p53 was phosphorylated rapidly at its Ser9 and Ser392 residues, but not at Ser15 or Ser20. Gene profile analysis of pre-miR-26a-transfected cells showed a significant increase in gene transcripts promoting apoptosis and p53 activation, with decreased levels of genes involved in cell-cycle progression. CONCLUSION: Delivery of miR-26a may represent a novel strategy for inhibiting pancreatic cancer growth, at least in part by enhancing phosphorylation of mutant p53 to restore its wild-type functions.
Authors: Oskar Franklin; Pär Jonsson; Ola Billing; Erik Lundberg; Daniel Öhlund; Hanna Nyström; Christina Lundin; Henrik Antti; Malin Sund Journal: Ann Surg Date: 2018-04 Impact factor: 12.969
Authors: Jossimar Coronel-Hernández; Eduardo López-Urrutia; Carlos Contreras-Romero; Izamary Delgado-Waldo; Gabriela Figueroa-González; Alma D Campos-Parra; Rebeca Salgado-García; Antonio Martínez-Gutierrez; Miguel Rodríguez-Morales; Nadia Jacobo-Herrera; Luis Ignacio Terrazas; Abraham Silva-Carmona; César López-Camarillo; Carlos Pérez-Plasencia Journal: Cancer Cell Int Date: 2019-04-02 Impact factor: 5.722