title: Onconase induces autophagy sensitizing pancreatic cancer cells to gemcitabine and activates Akt/mTOR pathway in a ROS-dependent manner.
abstract: Onconase® (ONC) is a member of the RNase super-family that is secreted in oocytes and early embryos of Rana pipiens. Over the last years, research interest about this small and basic frog RNase, also called ranpirnase, constantly increased because of its high cytotoxicity and anticancer properties. Onconase is currently used in clinical trials for cancer therapy; however, the precise mechanisms determining cytotoxicity in cancer cells have not yet been fully investigated. In the present manuscript, we evaluate the antitumoral property of onconase in pancreatic adenocarcinoma cells and in non-tumorigenic cells as a control. We demonstrate that ONC stimulates a strong antiproliferative and proapoptotic effect in cancer cells by reporting for the first time that ONC triggers Beclin1-mediated autophagic cancer cell death. In addition, ONC inhibits the expression of mitochondrial uncoupling protein 2 (UCP2) and of manganese-dependent superoxide dismutase (MnSOD) triggering mitochondrial superoxide ion production. ONC-induced reactive oxygen species (ROS) are responsible for Akt/mTOR pathway stimulation determining the sensitivity of cancer cells to mTOR inhibitors and lessening autophagic stimulation. This indicates ROS/Akt/mTOR axis as a strategy adopted by cancer cells to reduce ONC-mediated cytotoxic autophagy stimulation. In addition, we demonstrate that ONC can sensitize pancreatic cancer cells to the standard chemotherapeutic agent gemcitabine allowing a reduction of drug concentration when used in combination settings, thus suggesting a lowering of chemotherapy-related side effects. Altogether, our results shed more light on the mechanisms lying at the basis of ONC antiproliferative effect in cancer cells and support its potential use to develop new anticancer strategies.
authors.affiliation: Department of Life and Reproduction Sciences, Biochemistry Section, University of Verona, Verona, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fiorini
authors.affiliation: Department of Life and Reproduction Sciences, Biochemistry Section, University of Verona, Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Cordani
authors.affiliation: Department of Life and Reproduction Sciences, Biochemistry Section, University of Verona, Verona, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gotte
authors.affiliation: Department of Chemical Sciences, University of Naples "Federico II", Naples, Italy.
authors.forename: Delia
authors.initials: D
authors.lastname: Picone
authors.affiliation: Department of Life and Reproduction Sciences, Biochemistry Section, University of Verona, Verona, Italy. Electronic address: massimo.donadelli@univr.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Donadelli
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology; D012260:Ribonucleases / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D003841:Deoxycytidine; C546842:MTOR protein, human; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D012260:Ribonucleases; C058703:ranpirnase; D000093542:Gemcitabine
keywords: autophagy; gemcitabine; mammalian target of rapamycin (mTOR); onconase; pancreatic cancer; reactive oxygen species (ROS)