Survivin inhibitors mitigate chemotherapeutic resistance in breast cancer cells by suppressing genotoxic nuclear factor-kB activations

Wei Wang, Bo Zhang, Arul M. Mani, Zhongzhi Wu, Yu Fan, Wei Li, Zhaohui Wu

Research output: Contribution to journalArticle

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Abstract

Therapeutic resistance developed after chemotherapy and aggressive metastasis are the major causes of cancer-related death in patients with triple-negative breast cancer (TNBC). Survivin is the smallest member of the inhibitor-of-apoptosis proteins (IAPs) family, which plays critical roles in cell division and cell survival. High expression levels of survivin have been associated with therapeutic resistance in various cancers. We recently developed a novel small-molecule survivin inhibitor mimicking the IAP-binding motif of second mitochondriaderived activator of caspase, which showed high potency in promoting survivin degradation. Here, we show that survivin inhibitor MX106/MX107 suppresses TNBC cell proliferation. Moreover, MX106/MX107 synergized with chemotherapeutic drugs or radiation and significantly enhanced tumoricidal efficacy of genotoxic treatments. Mechanistically, MX106/MX107 induced degradation of XIAP and/or cIAP1, which inhibited nuclear factor kB (NF-kB) activation by genotoxic agents. Treatment with MX106/MX107 alone did not activate alternative NF-kB signaling in breast cancer cells, which is likely attributable to their selective potency in degrading survivin in these cells. In addition, survivin degradation by MX106/MX107 dramatically increased abnormal mitotic spindle formation and cell division failure, which led to cell cycle arrest in breast cancer cells. Overall, our study suggests that combination treatment of TNBC using survivin inhibitors MX106/MX107 with cytotoxic chemotherapeutic drugs can achieve significantly improved therapeutic efficacy, which depends on MX106/MX107-mediated inhibition of genotoxic NF-kB activation.

Original languageEnglish (US)
Pages (from-to)184-193
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume366
Issue number1
DOIs
StatePublished - Jul 1 2018

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Triple Negative Breast Neoplasms
Breast Neoplasms
Inhibitor of Apoptosis Proteins
Cell Division
Therapeutics
Amino Acid Motifs
Spindle Apparatus
Caspases
Cell Cycle Checkpoints
Protein Binding
Pharmaceutical Preparations
Neoplasms
Cell Survival
Cell Proliferation
Radiation
Neoplasm Metastasis
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Survivin inhibitors mitigate chemotherapeutic resistance in breast cancer cells by suppressing genotoxic nuclear factor-kB activations. / Wang, Wei; Zhang, Bo; Mani, Arul M.; Wu, Zhongzhi; Fan, Yu; Li, Wei; Wu, Zhaohui.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 366, No. 1, 01.07.2018, p. 184-193.

Research output: Contribution to journalArticle

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