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.
Highlights
Gastric cancer is currently the fourth most common malignancy worldwide and the third leading cause of cancer-related deaths in both males and females (Ferlay et al, 2015)
We show that aurora kinase A (AURKA) mediates phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) to promote protein translation of pro-oncogenic downstream effectors such as c-MYC and human double minute 2 (HDM2)
Acquired resistance to CDDP correlates with high levels of AURKA and p-eIF4E proteins in gastric cancer cells
Summary
Gastric cancer is currently the fourth most common malignancy worldwide and the third leading cause of cancer-related deaths in both males and females (Ferlay et al, 2015). Platinum-based regimens that include cisplatin [cis-diamminedichloroplatinum (CDDP)] are employed to treat a variety of cancers such as ovarian, bladder, esophageal, and gastric cancers. Platinum-based chemotherapeutic regimens have become standard approaches for the treatment of patients with advanced gastric cancer, there is a relatively low rate of complete response (Van Cutsem et al, 2008). There is an urgent need for the Abbreviations AURKA, aurora kinase A; CDDP, cisplatin or cis-diamminedichloroplatinum; CDDPR, cisplatin resistant; eIF4E, the eukaryotic translation initiation factor 4E; HDM2, human double minute 2; MLN8237, alisertib; siAURKA, small-interfering RNA of AURKA; siControl, smallinterfering RNA of scramble; sieIF4E, small-interfering RNA of eIF4E
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