Cyclin A1 expression and paclitaxel resistance in human ovarian cancer cells.
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.



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.



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.



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.
Laboratory of Gynecologic Oncology, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Boston, MA 02115, USA.
Kuan-Chun
KC
Huang
Laboratory of Gynecologic Oncology, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Boston, MA 02115, USA.
Junzheng
J
Yang
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Michelle C
MC
Ng
School of Medicine and Menzies Health Institute Queensland, Griffith University, Meadowbrook, Australia.
Shu-Kay
SK
Ng
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
William R
WR
Welch
Laboratory of Gynecologic Oncology, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Boston, MA 02115, USA.
Michael G
MG
Muto
Laboratory of Gynecologic Oncology, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Boston, MA 02115, USA.
Ross S
RS
Berkowitz
Laboratory of Gynecologic Oncology, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Boston, MA 02115, USA. Electronic address: sng@partners.org.
Shu-Wing
SW
Ng
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D016922:Cellular Senescence; D056750:Cyclin A1 / Q000235:genetics*; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D019204:GTP-Binding Proteins / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*; D017239:Paclitaxel / Q000627:therapeutic use*; D010750:Phosphoproteins / Q000235:genetics; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D011503:Transglutaminases / Q000235:genetics
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C503745:CCNA1 protein, human; D056750:Cyclin A1; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; D004317:Doxorubicin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D017239:Paclitaxel; D005472:Fluorouracil
Chemoresistance; Microarray; Ovarian cancer; Paclitaxel; Tumourigenesis
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