Abstract
DNA topoisomerase IIα (170 kDa, TOP2α/170) induces transient DNA double-strand breaks in proliferating cells to resolve DNA topological entanglements during chromosome condensation, replication, and segregation. Therefore, TOP2α/170 is a prominent target for anticancer drugs whose clinical efficacy is often compromised due to chemoresistance. Although many resistance mechanisms have been defined, acquired resistance of human cancer cell lines to TOP2α interfacial inhibitors/poisons is frequently associated with a reduction of Top2α/170 expression levels. Recent studies by our laboratory, in conjunction with earlier findings by other investigators, support the hypothesis that a major mechanism of acquired resistance to TOP2α-targeted drugs is due to alternative RNA processing/splicing. Specifically, several TOP2α mRNA splice variants have been reported which retain introns and are translated into truncated TOP2α isoforms lacking nuclear localization sequences and subsequent dysregulated nuclear-cytoplasmic disposition. In addition, intron retention can lead to truncated isoforms that lack both nuclear localization sequences and the active site tyrosine (Tyr805) necessary for forming enzyme-DNA covalent complexes and inducing DNA damage in the presence of TOP2α-targeted drugs. Ultimately, these truncated TOP2α isoforms result in decreased drug activity against TOP2α in the nucleus and manifest drug resistance. Therefore, the complete characterization of the mechanism(s) regulating the alternative RNA processing of TOP2α pre-mRNA may result in new strategies to circumvent acquired drug resistance. Additionally, novel TOP2α splice variants and truncated TOP2α isoforms may be useful as biomarkers for drug resistance, prognosis, and/or direct future TOP2α-targeted therapies.
Highlights
The human DNA topoisomerase IIα (170 kDa, TOP2α/170) enzyme functions as a homodimer with the active site Tyr805 residues in each subunit initiating reversible transesterification reactions to generate TOP2α/170-DNA covalent cleavage complexes[1,2,3,4]
Cisplatin/etoposide is first-line treatment for small cell lung cancer[12,13]; doxorubicin and epirubicin are used in combination with other drugs as a preoperative/adjuvant therapy regimen for the treatment of breast cancer[14,15]; and daunorubicin and mitoxantrone are used in treating acute myeloid leukemia (AML)[16,17]
This truncated TOP2α isoform and others generated from intron retention in T-cell lines were lacking the canonical nuclear localization signal (NLS) and all were detected in cytoplasmic extracts[34]
Summary
The human DNA topoisomerase IIα (170 kDa, TOP2α/170) enzyme functions as a homodimer with the active site Tyr805 residues in each subunit initiating reversible transesterification reactions to generate TOP2α/170-DNA covalent cleavage complexes[1,2,3,4]. Such seems to be the case with a number of documented TOP2α mRNA splice variants, which retain introns, are translated into truncated TOP2α isoforms, and play a role in mediating TOP2α poison chemoresistance in various cell lines[32,33,34,35,36]. Compared to parental HL-60 cells, HL60/MX2 cells contained reduced TOP2α/170 protein levels and expressed a novel truncated TOP2α isoform migrating at ~160 kDa (TOP2α/160) that localized predominantly to the cytoplasm .
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