Simultaneous inhibition of deubiquitinating enzymes (DUBs) and autophagy synergistically kills breast cancer cells

Rachel Isaksson Vogel, Kathleen Coughlin, Alessandra Scotti, Yoshie Iizuka, Ravi Anchoori, Richard B.S. Roden, Mauro Marastoni, Martina Bazzaro

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Breast cancer is one of the leading causes of cancer death among women in the United States. Patients expressing the estrogen and progesterone receptor (ER and PR) and human epidermal growth factor 2 (HER-2) tumor markers have favorable prognosis and efficacious therapeutic options. In contrast, tumors that are negative for these markers (triple-negative) have a disproportionate share of morbidity and mortality due to lack of a validated molecular target. Deubiquitinating enzymes (DUBs) are a critical component of ubiquitinproteasome- system degradation and have been shown to be differentially expressed and activated in a number of cancers, including breast, with their aberrant activity linked to cancer prognosis and clinical outcome. We evaluated the effect of the DUB inhibitors b-AP15 and RA-9 alone and in combination with early- and late-stage lysosomal inhibitors on cell viability in a panel of triple negative breast cancer (TNBC) cell lines. Our results indicate small-molecule DUB inhibitors have a profound effect on TNBC viability and lead to activation of autophagy as a cellular mechanism to compensate for ubiquitin-proteasome-system stress. Treatment with sub-optimal doses of DUB and lysosome inhibitors synergistically kills TNBC cells. This supports the evaluation of DUB inhibition, in combination with lysosomal inhibition, as a therapeutic approach for the treatment of TNBC.

Original languageEnglish (US)
Pages (from-to)4159-4170
Number of pages12
JournalOncotarget
Volume6
Issue number6
DOIs
StatePublished - 2015

Keywords

  • Autophagy
  • Breast Cancer
  • Deubiquitinating Enzymes
  • Proteasome Inhibitors
  • Triple Negative Breast Cancer

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