Gli family transcription factors are drivers of patupilone resistance in ovarian cancer.

Abstract

Epothilones constitute a novel class of antitubulin agents that are active in patients who relapse after treatment with other chemotherapeutics. This study investigated the molecular mechanisms leading to the onset of epothilone-B (patupilone) resistance in ovarian cancer. Results demonstrated that the Gli family of transcription factors was overexpressed in resistant cells and that treatment with a specific Gli1 inhibitor (GANT58) made cells more susceptible to treatment, partially reversing drug resistance. We also demonstrated that Gli1 knockdown halted growth in resistant cells that were exposed to patupilone, confirming that Gli1 is capable of directly mediating epothilone-B resistance. Another observation from our research was that patupilone-resistant cells produced HGF and acquired characteristics of a mesenchymal phenotype. However, HGF silencing alone was not capable of converting the drug-resistant phenotype to a susceptible one, and in this case we demonstrated that Gli1 overexpression led to an increase in HGF, establishing a functional link between Gli1 and HGF. These results demonstrated that Gli1 played a key role in driving resistance to patupilone, suggesting that the combination of epothilones and Gli1-targeted agents could be exploited to improve outcomes in ovarian cancer patients resistant to standard treatments.

• Authors: Simona Mozzetti, Enrica Martinelli, Giuseppina Raspaglio, Silvia Prislei, Marta De Donato, Flavia Filippetti, Shohreh Shahabi, Giovanni Scambia, Cristiano Ferlini
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 84 Issue 11 Pg. 1409-18 (Dec 01 2012) ISSN: 1873-2968 [Electronic] England
• PMID: 22964220 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• DNA Primers
• Epothilones
• Transcription Factors
• epothilone B

Topics

• Antineoplastic Agents (therapeutic use)
• Base Sequence
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• DNA Primers
• Drug Resistance, Neoplasm
• Enzyme-Linked Immunosorbent Assay
• Epithelial-Mesenchymal Transition
• Epothilones (therapeutic use)
• Female
• Humans
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Real-Time Polymerase Chain Reaction
• Transcription Factors (physiology)