ABSTRACT
PURPOSE: The HOX genes are a family of homeodomain containing transcription factors that determine embryonic tissue identity and also have regulatory and oncogenic roles in adult cells. We quantified the expression of HOX genes in normal kidney tissue, primary tumors and derived cell lines, and examined their role in renal cancer cell survival. MATERIALS AND METHODS: Quantitative polymerase chain reaction was used to evaluate HOX gene expression in cells and tissues. HOX gene function was disrupted using a peptide that blocks the interaction between HOX proteins and their PBX cofactor. Apoptosis was assessed by annexin/propidium iodide staining and direct measurement of caspase activity. RESULTS: Primary renal tumors and derived cell lines showed abnormal HOX gene expression. Furthermore, blocking HOX activity by targeting the interaction between HOX and its cofactor PBX caused apoptotic and necrotic cell death in the renal cancer cell lines CaKi-2 and 769-P, while sparing normal adult kidney cells. CONCLUSIONS: Our findings suggest that the HOX/PBX dimer is a potential therapeutic target in renal cancer.
Subject(s)
Apoptosis/genetics , Gene Expression Regulation, Neoplastic , Genes, Homeobox/physiology , Transcription Factors/genetics , Animals , Carcinoma, Renal Cell/genetics , Cell Death/genetics , Cell Line, Tumor , Kidney Neoplasms/genetics , Mice , Necrosis/pathology , RNA, Neoplasm/analysis , Reference Values , Reverse Transcriptase Polymerase Chain Reaction , Sensitivity and SpecificityABSTRACT
Malignant melanoma is a cancer that arises from melanocyte cells in a complex but well-studied process, and which can only be successfully treated prior to metastasis as it is highly resistant to conventional therapies. A number of recent reports have indicated that members of the HOX family of homeodomain-containing transcription factors are deregulated in melanoma, and may actually be required to maintain proliferation. In this report, we describe the use of a novel, cell-permeable antagonist of the interaction between HOX proteins and PBX, a second homeodomain-containing transcription factor that modifies HOX activity. This antagonist can block the growth of murine B16 cells and trigger apoptosis both in vitro and in vivo when administered to mice with flank tumors.
