Targeting chemoresistance in Xp11.2 translocation renal cell carcinoma using a novel polyamide-chlorambucil conjugate

Author:

Funasaki, Shintaro

Mehanna, Sally

Ma, Wenjuan

Nishizawa, Hidekazu

Kamikubo, Yasuhiko [ORCID]

Sugiyama, Hiroshi

Ikeda, Shuji

Motoshima, Takanobu

Hasumi, Hisashi [ORCID]

Linehan, W Marston

Schmidt,Laura

Ricketts, Chris

Suda, Toshio

Oike, Yuichi

Kamba, Tomomi

Baba, Masaya [ORCID]
Author Address

Laboratory of Cancer Metabolism, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan., Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan., Department of Human Health Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Department of Chemistry, Graduate School of Science, Kyoto University, Japan., Department of Urology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan., Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, USA., Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA., Laboratory of Stem Cell Regulation, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan., Cancer Science Institute of Singapore, National University of Singapore; Centre for Translational Medicine, Singapore, 117599, Singapore., Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.,

Abstract:

Renal cell carcinoma with Xp11.2 translocation involving TFE3 gene (TFE3-RCC) is a recently identified subset of RCC with unique morphology and clinical presentation. The chimeric PRCC-TFE3 protein produced by Xp11.2 translocation has been shown to transcriptionally activate its downstream target genes that play important roles in carcinogenesis and tumor development of TFE3-RCC. However, the underlying molecular mechanisms remain poorly understood. Here we show that in TFE3-RCC cells, PRCC-TFE3 controls heme oxygenase 1 (HMOX1) expression to confer chemoresistance. Inhibition of HMOX1 sensitized the PRCC-TFE3 expressing cells to genotoxic reagents. We screened for a novel chlorambucil-polyamide conjugate (Chb) to target PRCC-TFE3 dependent transcription, and identified Chb16 as a PRCC-TFE3-dependent transcriptional inhibitor of HMOX1 expression. Treatment of the patient derived cancer cells with Chb16 exhibited senescence and growth arrest, and increased sensitivity of the TFE3-RCC cells to the genotoxic reagent etoposide. Thus, our data showed that the TFE3-RCC cells acquired chemoresistance through HMOX1 expression and that inhibition of HMOX1 by Chb16 may be an effective therapeutic strategy for TFE3-RCC. This article is protected by copyright. All rights reserved.

See More

Author Address