Selective inhibitors of nuclear export (SINE) as novel therapeutics for prostate cancer

Janet Mendonca, Anup Sharma, Hae Soo Kim, Hans Hammers, Alan Meeker, Angelo De Marzo, Michael Carducci, Michael Kauffman, Sharon Shacham, Sushant Kachhap

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Mislocalization of proteins is a common feature of cancer cells. Since localization of proteins is tightly linked to its function, cancer cells can inactivate function of a tumor suppressor protein through mislocalization. The nuclear exportin CRM1/XPO 1 is upregulated in many cancers. Targeting XPO 1 can lead to nuclear retention of cargo proteins such as p53, Foxo, and BRCA1 leading to cell cycle arrest and apoptosis. We demonstrate that selective inhibitors of nuclear export (SINE) can functionally inactivate XPO 1 in prostate cancer cells. Unlike the potent, but toxic, XPO 1 inhibitor leptomycin B, SINE inhibitors (KPT-185, KPT-330, and KPT-251) cause a decrease in XPO 1 protein level through the proteasomal pathway. Treatment of prostate cancer cells with SINE inhibitors lead to XPO 1 inhibition, as evaluated by RevGFP export assay, leading to nuclear retention of p53 and Foxo proteins, consequently, triggering apoptosis. Our data reveal that treatment with SINE inhibitors at nanomolar concentrations results in decrease in proliferation and colonogenic capacity of prostate cancer cells by triggering apoptosis without causing any cell cycle arrest. We further demonstrate that SINE inhibitors can be combined with other chemotherapeutics like doxorubicin to achieve enhanced growth inhibition of prostate cancer cells. Since SINE inhibitors offer increased bioavailability, reduced toxicity to normal cells, and are orally available they can serve as effective therapeutics against prostate cancer. In conclusion, our data reveals that nucleocytoplasmic transport in prostate cancer can be effectively targeted by SINE inhibitors.

Original languageEnglish (US)
Pages (from-to)6102-6112
Number of pages11
JournalOncotarget
Volume5
Issue number15
StatePublished - Jan 1 2014

Fingerprint

Cell Nucleus Active Transport
Prostatic Neoplasms
Therapeutics
Apoptosis
Cell Cycle Checkpoints
Proteins
Karyopherins
Tumor Suppressor Proteins
Neoplasms
Poisons
Doxorubicin
Biological Availability
Growth

Keywords

  • CRM1
  • Nucleocytoplasmic transport
  • Prostate cancer
  • SINE inhibitors
  • XPO 1

ASJC Scopus subject areas

  • Oncology

Cite this

Mendonca, J., Sharma, A., Kim, H. S., Hammers, H., Meeker, A., Marzo, A. D., ... Kachhap, S. (2014). Selective inhibitors of nuclear export (SINE) as novel therapeutics for prostate cancer. Oncotarget, 5(15), 6102-6112.

Selective inhibitors of nuclear export (SINE) as novel therapeutics for prostate cancer. / Mendonca, Janet; Sharma, Anup; Kim, Hae Soo; Hammers, Hans; Meeker, Alan; Marzo, Angelo De; Carducci, Michael; Kauffman, Michael; Shacham, Sharon; Kachhap, Sushant.

In: Oncotarget, Vol. 5, No. 15, 01.01.2014, p. 6102-6112.

Research output: Contribution to journalArticle

Mendonca, J, Sharma, A, Kim, HS, Hammers, H, Meeker, A, Marzo, AD, Carducci, M, Kauffman, M, Shacham, S & Kachhap, S 2014, 'Selective inhibitors of nuclear export (SINE) as novel therapeutics for prostate cancer', Oncotarget, vol. 5, no. 15, pp. 6102-6112.
Mendonca J, Sharma A, Kim HS, Hammers H, Meeker A, Marzo AD et al. Selective inhibitors of nuclear export (SINE) as novel therapeutics for prostate cancer. Oncotarget. 2014 Jan 1;5(15):6102-6112.
Mendonca, Janet ; Sharma, Anup ; Kim, Hae Soo ; Hammers, Hans ; Meeker, Alan ; Marzo, Angelo De ; Carducci, Michael ; Kauffman, Michael ; Shacham, Sharon ; Kachhap, Sushant. / Selective inhibitors of nuclear export (SINE) as novel therapeutics for prostate cancer. In: Oncotarget. 2014 ; Vol. 5, No. 15. pp. 6102-6112.
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