Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties

A. N. Paranjape, R. Soundararajan, S. J. Werden, R. Joseph, J. H. Taube, H. Liu, J. Rodriguez-Canales, N. Sphyris, I. Wistuba, N. Miura, J. Dhillon, N. Mahajan, K. Mahajan, J. T. Chang, M. Ittmann, S. N. Maity, C. Logothetis, D. G. Tang, S. A. Mani

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Advanced prostate adenocarcinomas enriched in stem-cell features, as well as variant androgen receptor (AR)-negative neuroendocrine (NE)/small-cell prostate cancers are difficult to treat, and account for up to 30% of prostate cancer-related deaths every year. While existing therapies for prostate cancer such as androgen deprivation therapy (ADT), destroy the bulk of the AR-positive cells within the tumor, eradicating this population eventually leads to castration-resistance, owing to the continued survival of AR-/lo stem-like cells. In this study, we identified a critical nexus between p38MAPK signaling, and the transcription factor Forkhead Box Protein C2 (FOXC2) known to promote cancer stem-cells and metastasis. We demonstrate that prostate cancer cells that are insensitive to ADT, as well as high-grade/NE prostate tumors, are characterized by elevated FOXC2, and that targeting FOXC2 using a well-tolerated p38 inhibitor restores epithelial attributes and ADT-sensitivity, and reduces the shedding of circulating tumor cells in vivo with significant shrinkage in the tumor mass. This study thus specifies a tangible mechanism to target the AR-/lo population of prostate cancer cells with stem-cell properties.

Original languageEnglish
Pages (from-to)5963-5976
Number of pages14
JournalOncogene
Volume35
Issue number46
DOIs
StatePublished - Nov 17 2016

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