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

• Type of Material: Article
• Authors: Purnachandra Ganji, Emory University; Olatunji Alese, Emory University; Jerome Landry, Emory University; Roberto Diaz, University of South Florida; Bassel El-Rayes, Emory University
• Language: English
• Date: 2014-10-30
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: @ 2016 Impact Journals, LLC
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.2484
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 5
• Issue: 20
• Start Page: 9980
• End Page: 9991
• Grant/Funding Information: This work was partially funded from Emory University's Open Access Publishing Fund.
• Keywords: GROWTH-FACTOR RECEPTOR; Oncology; Hsp90; CETUXIMAB PLUS IRINOTECAN; Science & Technology; RESISTANCE; C-MYC; Colon cancer; ANTITUMOR-ACTIVITY; Life Sciences & Biomedicine; COLON-CANCER; cell cycle progression and chemotherapy; EXPRESSION PREDICTS; GANETESPIB; FLUOROURACIL; ganetespib; Cell Biology; FACTOR-I RECEPTOR
• Research Categories: Health Sciences, Radiology; Health Sciences, Oncology; Health Sciences, General

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 (50nM) 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 5FUbased chemotherapy. Combining HSP90 inhibitors with chemotherapy is a rational approach for future drug development in CRC.