Distinguishing between cancer cell differentiation and resistance induced by all-trans retinoic acid using transcriptional profiles and functional pathway analysis

All-trans retinoic acid (ATRA) induces differentiation in various cell types and has been investigated extensively for its effective use in cancer prevention and treatment. Relapsed or refractory disease that is resistant to ATRA is a clinically significant problem. To identify the molecular mechanism that bridges ATRA differentiation and resistance in cancer, we selected the multidrug-resistant leukemia cell line HL-60[R] by exposing it to ATRA, followed by sequential increases of one-half log concentration. A cytotoxicity analysis revealed that HL-60[R] cells were highly resistant to ATRA, doxorubicin, and etoposide. A comparative genome hybridization analysis of HL-60[R] cells identified gains of 4q34, 9q12, and 19q13 and a loss of Yq12 compared with in the parental HL-60 cell line. Transcriptional profiles and functional pathway analyses further demonstrated that 7 genes (FEN1, RFC5, EXO1, XRCC5, PARP1, POLR2F, and GTF2H3) that were relatively up-regulated in HL-60[R] cells and repressed in cells with ATRA-induced differentiation were related to mismatch repair in eukaryotes, DNA double-strand break repair, and nucleotide excision repair pathways. Our results suggest that transcriptional time series profiles and a functional pathway analysis of drug resistance and ATRA-induced cell differentiation will be useful for identifying promyelocytic leukemia patients who are eligible for new therapeutic strategies.