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Pituitary homeobox 2 (PITX2) protects renal cancer cell lines against doxorubicin toxicity by transcriptional activation of the multidrug transporter ABCB1
Author(s) -
Lee WingKee,
Chakraborty Prabir Kumar,
Thévenod Frank
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.471.3
Subject(s) - cancer research , biology , pitx2 , transcription factor , gene silencing , chromatin immunoprecipitation , homeobox , microbiology and biotechnology , gene expression , promoter , gene , genetics
The multidrug resistance (MDR) P‐glycoprotein ABCB1 plays a major role in MDR of malignant cells and is regulated by various transcription factors, including Wnt/β‐catenin/TCF4. The transcription factor PITX2 (Pituitary homeobox‐2) is essential for embryonic development. PITX2 operates by recruiting and interacting with β‐catenin to increase the expression of growth‐regulating genes, such as cyclin D1/2 and c‐Myc. The importance of PITX2 in malignancy is not yet known. Here, in the renal cancer cell lines ACHN and A498, ABCB1 expression correlates with nuclear PITX2 localization and PITX2‐luciferase reporter gene activity (A498 >; ACHN). PITX2 overexpression increases ABCB1 expression and cell survival in ACHN cells. Silencing of PITX2 by siRNA down‐regulates ABCB1 and induces a greater chemotherapeutic response to doxorubicin in A498 cells, as determined by MTT cell viability and clonogenic survival assays. Two PITX2 binding sequences were identified in the ABCB1 promoter sequence. PITX2 binding was confirmed by chromatin immunoprecipitation. Beta‐catenin is not required for PITX2 upregulation of ABCB1 since ABCB1 mRNA increased and doxorubicin toxicity decreased upon PITX2 overexpression in β‐ catenin −/− cells. The data show for the first time that ABCB1 is a target gene of PITX2 transcriptional activity, promoting MDR and cell survival. Funded by DFG and Westermann‐Westdorp Foundation, Germany.