Importins and exportins as therapeutic targets in cancer

Amit Mahipal, Mokenge Malafa

Research output: Contribution to journalReview article

49 Citations (Scopus)

Abstract

The nuclear transport proteins, importins and exportins (karyopherin-β proteins), may play an important role in cancer by transporting key mediators of oncogenesis across the nuclear membrane in cancer cells. During nucleocytoplasmic transport of tumor suppressor proteins and cell cycle regulators during the processing of these proteins, aberrant cellular growth signaling and inactivation of apoptosis can occur, both critical to growth and development of tumors. Karyopherin-β proteins bind to these cargo proteins and RanGTP for active transport across the nuclear membrane through the nuclear pore complex. Importins and exportins are overexpressed in multiple tumors including melanoma, pancreatic, breast, colon, gastric, prostate, esophageal, lung cancer, and lymphomas. Furthermore, some of the karyopherin-β proteins such as exportin-1 have been implicated in drug resistance in cancer. Importin and exportin inhibitors are being considered as therapeutic targets against cancer and have shown preclinical anticancer activity. Moreover, synergistic activity has been observed with various chemotherapeutic and targeted agents. However, clinical development of the exportin-1 inhibitor leptomycin B was stopped due to adverse events, including vomiting, anorexia, and dehydration. Selinexor, a selective nuclear export inhibitor, is being tested in multiple clinical trials both as a single agent and in combination with chemotherapy. Selinexor has demonstrated clinical activity in multiple cancers, especially acute myelogenous leukemia and multiple myeloma. The roles of other importin and exportin inhibitors still need to be investigated clinically. Targeting the key mediators of nucleocytoplasmic transport in cancer cells represents a novel strategy in cancer intervention with the potential to significantly affect outcomes.

Original languageEnglish (US)
Pages (from-to)135-143
Number of pages9
JournalPharmacology and Therapeutics
Volume164
DOIs
StatePublished - Aug 1 2016

Fingerprint

Karyopherins
Cell Nucleus Active Transport
Neoplasms
Therapeutics
Nuclear Envelope
Proteins
Tumor Suppressor Proteins
Nuclear Pore
Active Biological Transport
Anorexia
Esophageal Neoplasms
Nuclear Proteins
Combination Drug Therapy
Multiple Myeloma
Growth and Development
Dehydration
Drug Resistance
Acute Myeloid Leukemia
Vomiting
Prostate

Keywords

  • Exportin
  • Exportin-1
  • Importin
  • Karyopherins
  • Neoplasm
  • Nucleocytoplasmic transport

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Importins and exportins as therapeutic targets in cancer. / Mahipal, Amit; Malafa, Mokenge.

In: Pharmacology and Therapeutics, Vol. 164, 01.08.2016, p. 135-143.

Research output: Contribution to journalReview article

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