CRM1-Mediated Nuclear Export of Proteins and Drug Resistance in Cancer

Joel   G.   Turner; Daniel   M.   Sullivan

Abstract

Expression levels of intact tumor suppressor proteins and molecular targets of anti-neoplastic agents are critical in defining cancer cell drug sensitivity; however, the intracellular location of a specific protein may be as important. Many tumor suppressor proteins must be present in the cell nucleus to perform their policing activities or for the cell to respond to chemotherapeutic agents. Nuclear proteins needed to prevent cancer initiation or progression or to optimize chemotherapeutic response include the tumor suppressor proteins p53, APC/β-catenin, and FOXO family genes; negative regulators of cell cycle progression and survival such as p21CIP1and p27KIP1; and chemotherapeutic targets such as DNA topoisomerases I and IIα. Mislocalization of a nuclear protein into the cytoplasm can render it ineffective as a tumor suppressor or as a target for chemotherapy. Blocking nuclear export of any or all of these proteins may restore tumor suppression or apoptosis or, for topoisomerases I and IIα, reverse drug resistance to inhibitors of these enzymes. During disease progression or in response to the tumor environment, cancer cells appear to acquire intracellular mechanisms to export anti-cancer nuclear proteins. These mechanisms generally involve modification of nuclear proteins, causing the proteins to reveal leucine-rich nuclear export signal protein sequences. Subsequent export is mediated by CRM1. This review defines the general processes involved in nuclear export mediated by CRM1/RanGTP (exportin/XPO1), examines the functions of individual tumor suppressor nuclear proteins and nuclear targets of chemotherapy, and explores potential mechanisms of cancer cells to induce export of these proteins. Novel drugs that could potentially counteract nuclear export of specific proteins are also discussed.

Keywords: CRM1, drug resistance, topoisomerase I, topoisomerase IIα, p53, APC/β-catenin, FOXO, P21cip1, p27KIP1