Open AccessTargeting chemoresistance in Xp11.2 translocation renal cell carcinoma using a novel polyamide–chlorambucil conjugate
Author(s) -
Funasaki Shintaro,
Mehanna Sally,
Ma Wenjuan,
Nishizawa Hidekazu,
Kamikubo Yasuhiko,
Sugiyama Hiroshi,
Ikeda Shuji,
Motoshima Takanobu,
Hasumi Hisashi,
Linehan W. Marston,
Schmidt Laura S.,
Ricketts Chris,
Suda Toshio,
Oike Yuichi,
Kamba Tomomi,
Baba Masaya
Publication year - 2022
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.15364
Subject(s) - tfe3 , hmox1 , cancer research , renal cell carcinoma , chromosomal translocation , biology , chemistry , gene expression , medicine , pathology , gene , biochemistry , heme oxygenase , heme , promoter , enzyme
Renal cell carcinoma with Xp11.2 translocation involving the 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.