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se·nes·cence
səˈnesəns/ noun
Biology
noun: senescence
- the condition or process of deterioration with age.
- loss of a cell's power of division and growth.
abstract
Highlights
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- Elevated cyclin A1 expression is negatively associated with relapse time of ovarian cancer patients.
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- Ectopic expression of cyclin A1 in ovarian cancer cells suppresses paclitaxel-induced apoptosis.
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- However, cyclin A1-overexpression slows down cell proliferation and induces premature senescence.
Background
The
development of intrinsic and acquired resistance to antineoplastic
agents is a major obstacle to successful chemotherapy in ovarian
cancers. Identification and characterisation of chemoresponse-associated
biomarkers are of paramount importance for novel therapeutic
development.
Methods
Global
RNA expression profiles were obtained by high-throughput microarray
analysis. Cell cycle, proliferation rate, and paclitaxel sensitivity of
ovarian cancer cells harbouring cyclin A1-inducible expression construct
were compared with and without tetracycline induction, as well as when
the cyclin A1 expression was suppressed by short inhibiting RNA (siRNA).
Cellular senescence was evaluated by β-galactosidase activity staining.
Results
Global
RNA expression profiling and subsequent correlation studies of gene
expression level and drug response has identified that elevated
expression of cyclin A1 (CCNA1) was significantly associated with
cellular resistance to paclitaxel, doxorubicin and 5-fluorouracil. The
role of cyclin A1 in paclitaxel resistance was confirmed in ovarian
cancer cells that harbour an inducible cyclin A1 expression construct,
which showed reduced paclitaxel-mediated growth inhibition and apoptosis
when cyclin A1 expression was induced, whereas downregulation of cyclin
A1 expression in the same cell lines using cyclin A1-specific siRNAs
sensitised the cells to paclitaxel toxicity. However, ovarian cancer
cells with ectopic expression of cyclin A1 demonstrated slowdown of
proliferation and senescence-associated β-galactosidase activity.
Conclusions
Our
profiling and correlation studies have identified cyclin A1 as one
chemoresistance-associated biomarker in ovarian cancer. The results of
the characterisation studies suggest that cyclin A1 functions as an
oncogene that controls proliferative and survival activities in
tumourigenesis and chemoresistance of ovarian cancer.
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