Cisplatin-resistant cancer cells are sensitive to Aurora kinase A inhibition by alisertib

Lihong Wang, Janet Arras, Ahmed Katsha, Saif Hamdan, Abbes Belkhiri, Jeffrey Ecsedy, Wael El-Rifai

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

De novo and acquired resistance to platinum therapy such as cisplatin (CDDP) is a clinical challenge in gastric cancer treatment. Aberrant expression and activation of aurora kinase A (AURKA) and eukaryotic translation initiation factor 4E (eIF4E) are detected in several cancer types. Herein, we investigated the role of AURKA in CDDP resistance in gastric cancer. Western blot analysis demonstrated overexpression of AURKA and phosphorylation of eIF4E in acquired and de novo CDDP-resistant gastric cancer models. Inhibition of AURKA with MLN8237 (alisertib) alone or in combination with CDDP significantly suppressed viability of CDDP-resistant cancer cells (P < 0.01). Additionally, inhibition or knockdown of AURKA decreased protein expression of p-eIF4E (S209), HDM2, and c-MYC in CDDP-resistant cell models. This was associated with a significant decrease in cap-dependent translation levels (P < 0.01). In vivo tumor xenografts data corroborated these results and confirmed that inhibition of AURKA was sufficient to overcome CDDP resistance in gastric cancer. Our data demonstrate that AURKA promotes acquired and de novo resistance to CDDP through regulation of p-eIF4E (S209), c-MYC, HDM2, and cap-dependent translation. Targeting AURKA could be an effective therapeutic approach to overcome CDDP resistance in refractory gastric cancer and possibly other cancer types.

Original languageEnglish (US)
Pages (from-to)981-995
Number of pages15
JournalMolecular Oncology
Volume11
Issue number8
DOIs
StatePublished - Aug 1 2017
Externally publishedYes

Keywords

  • alisertib
  • cisplatin
  • eIF4E
  • HDM2
  • MLN8237
  • MYC

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cancer Research

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