HSP90 inhibition downregulates thymidylate synthase and sensitizes colorectal cancer cell lines to the effect of 5FU-based chemotherapy

Ganji Purnachandra Nagaraju,Jerome Landry,Olatunji B. Alese,Roberto Diaz,Bassel F. El-Rayes

doi:10.18632/oncotarget.2484

Ganji Purnachandra Nagaraju, Jerome Landry + Show 3 more

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https://doi.org/10.18632/oncotarget.2484

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Abstract

Cell cycle progression and DNA synthesis are essential steps in cancer cell growth. Thymidylate synthase (TS) is a therapeutic target for 5FU. We tested the hypothesis that HSP90 transcriptional and functional inhibition can inhibit cell cycle progression, downregulate TS levels and sensitize colorectal cancer (CRC) cell lines to the effects of 5FU. Treatment with ganetespib (50 nM) for 24 hours inhibited cyclin D1 and pRb at the transcriptional and translational levels and induced p21, leading to G0/G1 cell cycle arrest in both CRC cell lines (HCT-116 and HT-29). This was associated with downregulation of E2F1 and its target gene TS. In addition, ganetespib inhibited PI3K/Akt and ERK signalling pathways. Similar effects were observed with HSP90 knockdown in both cell lines. Ganetespib sensitized CRC cell lines to the effects of oxaliplatin and 5FU. Similar effects were also observed in tumors from animals treated with ganetespib, oxaliplatin and 5FU. In this study, we present in vitro and animal data supporting that the targeting of HSP90 decreases CRC cell survival and proliferation. Ganetespib sensitizes CRC cell lines to the effects of 5FU-based chemotherapy. Combining HSP90 inhibitors with chemotherapy is a rational approach for future drug development in CRC.

Highlights

Colorectal cancer (CRC) is the second leading cause of mortality in the United States [1]
The protein and mRNA expression levels of CDK4 and cyclin D1 were significantly decreased in ganetespib treated CRC cells compared to controls in both cell lines (Fig. 1C & D)
Proliferative signalling pathways downstream of the epidermal growth factor receptor (EGFR) and IGF-1R are commonly dysregulated in CRC [10]

Summary

Introduction

Colorectal cancer (CRC) is the second leading cause of mortality in the United States [1]. Inhibition of the epidermal growth factor receptor (EGFR) has been shown in clinical settings to restore sensitivity to cytotoxic chemotherapy [6]. This suggests that the EGFR pathway contributes to chemoresistance [7]. In preclinical CRC models, activation of EGFR, IGFR or their downstream signalling pathways involving Ras, Raf, or Akt leads to increased proliferation and resistance to therapy [11], [12]. Growth promoting signals through these pathways www.impactjournals.com/oncotarget lead to activation of c-myc and cyclin D1 [11], [13] This in turn results in phosphorylation of retinoblastoma (Rb), releasing E2F transcriptional factors [14]. Activation of E2F1 may provide a common pathway that explains at a molecular level the relationship between proliferation and resistance to therapy

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