The Novel C-terminal Truncated 90-kDa Isoform of Topoisomerase IIα (TOP2α/90) Is a Determinant of Etoposide Resistance in K562 Leukemia Cells via Heterodimerization with the TOP2α/170 Isoform

Kanagasabai, Ragu; Karmahapatra, Soumendrakrishna; Kientz, Corey A.; Yu, Yang; Hernández, Víctor Agmo; Kania, Evan E; Yalowich, Jack C.; Elton, Terry S.

doi:10.1124/mol.117.111567

Cited by 12 publications

(76 citation statements)

References 52 publications

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“…The location of the human TOP2A gene is on chromosome 17, and its expression is associated with cell proliferation and the cell cycle; its production and degradation are regulated by the cell cycle, and it decreases rapidly after completing mitosis (11,12). Previous studies have reported that the accumulation of the TOP2A protein occurs due to the stable upregulation of TOP2A transcription (13,14).…”

Section: Introductionmentioning

confidence: 99%

High expression of TOP2A in hepatocellular carcinoma is associated with disease progression and poor prognosis

et al. 2020

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Hepatocellular carcinoma (HCC) is a common malignant tumor in the clinic. Although there are increasing numbers of available treatment methods, their therapeutic effects are not satisfactory. The clinical indicators commonly used to predict the prognosis of HCC include tumor size, degree of cirrhosis, degree of tumor differentiation and tumor microvascular invasion; however, there are currently no molecular indicators that can predict the prognosis of HCC. Due to the differences in the progression of liver cancer among individuals, there is a growing need for prognostic biomarkers to accurately stratify patients for appropriate risk-adaptive treatment. The DNA topoisomerase 2-α (TOP2A) gene, which is located on human chromosome 17, encodes DNA topoisomerase IIα. Previous studies have demonstrated that TOP2A indicates a poor prognosis in patients with various types of tumors, but no such studies are currently available on HCC. By analyzing the differential expression of TOP2A in 50 pairs of tumor and paracancerous tissue samples in The Cancer Genome Atlas (TCGA) database, the present study revealed that the expression of TOP2A was significantly higher in tumor tissue compared with that in paracancerous tissue (P=6.319x10-16). In the collected clinical samples, the mRNA expression levels of TOP2A were significantly upregulated in HCC tumor tissues compared with those in the paracancerous tissues (P=6.40x10-3), suggesting that TOP2A was associated with the occurrence and development of liver cancer. In addition, the associations between TOP2A expression, clinicopathological features and prognosis were analyzed using a multi-center large sample dataset from TCGA database, and the results demonstrated that high expression of TOP2A was associated with a higher T stage, poorer clinical stage and higher histological grade compared with those in patients with low TOP2A expression. High expression of TOP2A was also identified to be associated with a poor prognosis of HCC, particularly in Asian populations. These results suggested that high expression of TOP2A in HCC tissues may be closely associated with tumor progression and metastasis, which may be used as a biological indicator to predict tumor prognosis in clinical practice.

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Section: Introductionmentioning

confidence: 99%

High expression of TOP2A in hepatocellular carcinoma is associated with disease progression and poor prognosis

et al. 2020

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“…As melphalan‐induced DNA damages include both single‐ and double‐strand breaks (SSB and DSB, respectively), alkaline (pH13) single‐cell electrophoresis (comet) assays were used to evaluate the “overall” DNA damage in melphalan‐treated MM cells. In comparison with neutral comet assay that is typically used to detect DSB, alkaline comet assay appears to be more sensitive in detecting smaller amounts of damage including both SSB and DSB . The experiments were conducted following the manufacturer's instructions (CometAssay Kit #4250‐050‐K; Trevigen, Gaithersburg, MD).…”

Section: Methodsmentioning

confidence: 99%

“…In comparison with neutral comet assay that is typically used to detect DSB, alkaline comet assay appears to be more sensitive in detecting smaller amounts of damage including both SSB and DSB. 23 analyzed. Experiments were repeated for at least three times.…”

Section: Melphalan-induced Dna Damagementioning

confidence: 99%

XRCC1‐mediated DNA repair is associated with progression‐free survival of multiple myeloma patients after autologous stem cell transplant

Persaud

Johnson

Seligson

et al. 2019

Molecular Carcinogenesis

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Autologous stem cell transplant (ASCT) with high‐dose melphalan (HDM) is the standard treatment for fit multiple myeloma (MM) patients. It is generally believed that some DNA repair proteins impact the activity to repair melphalan‐induced DNA damage, thus potentially contributing to the patient's clinical response. However, knowledge of these proteins is limited. In the current study, we investigated the roles of XRCC1, a protein involved in base excision repair and single‐strand break repair, in melphalan response in MM cells. Small interfering RNA knockdown of XRCC1 significantly increased the accumulation of melphalan‐induced DNA damage in MM cells and sensitized them to melphalan treatment, indicating that genetic variation in XRCC1 may impact response to melphalan treatment. We then evaluated the association between an XRCC1 variant with reduced activity, rs25487 (R399Q), and clinical outcomes of 108 MM patients with melphalan therapy. Our results showed that XRCC1 rs25487 was associated with prolonged progression‐free survival (PFS) in MM patients. The adjusted hazard ratio for PFS between patients carrying rs25487 AA/AG and GG was 0.42 (95% confidence interval: 0.25, 0.84, P = .014). Taken together, these results indicate that XRCC1 is involved in the repair of melphalan‐induced DNA damage and XRCC1 rs25487 variant with impaired DNA repair function influences the clinical responses of HDM in MM patients.

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“…However, some intron-retaining mRNA transcripts leave the nucleus and undergo translation to produce new protein isoforms with novel functions [28][29][30][31] . 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] .…”

Section: Alternative Splicingmentioning

confidence: 99%

“…Several acquired and innate resistant models have been reported, which involve intron retention due to alternative RNA processing of TOP2α mRNA [32][33][34][35][36] . Harker et al [50] generated a mitoxantrone resistant human AML (HL-60) cell line designated HL-60/MX2 (35-fold resistant), by stepwise drug exposure from 1.7 to 170 nM.…”

Section: Top2α/160 (Intron 33 Retention) and Chemoresistancementioning

confidence: 99%

Effects of DNA topoisomerase IIα splice variants on acquired drug resistance

Elton¹,

Özer²,

Yalowich³

2020

CDR

Self Cite

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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.

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The Novel C-terminal Truncated 90-kDa Isoform of Topoisomerase IIα (TOP2α/90) Is a Determinant of Etoposide Resistance in K562 Leukemia Cells via Heterodimerization with the TOP2α/170 Isoform

Cited by 12 publications

References 52 publications

High expression of TOP2A in hepatocellular carcinoma is associated with disease progression and poor prognosis

High expression of TOP2A in hepatocellular carcinoma is associated with disease progression and poor prognosis

XRCC1‐mediated DNA repair is associated with progression‐free survival of multiple myeloma patients after autologous stem cell transplant

Effects of DNA topoisomerase IIα splice variants on acquired drug resistance

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