A BTB/POZ gene, NAC-1, a tumor recurrence-associated gene, as a potential target for Taxol resistance in ovarian cancer.
OBJECTIVE
We previously determined that NAC-1, a transcription factor and member of the BTB/POZ gene family, is associated with recurrent ovarian carcinomas. In the current study, we investigated further the relationship between NAC-1 expression and ovarian cancer.


METHODS
NAC-1 expression was assessed by immunohistochemistry, and clinical variables were collected by retrospective chart review. SiRNA system and NAC-1 gene transfection were used to asses NAC-1 function in Taxol resistance in vivo.


RESULTS
Overexpression of NAC-1 correlated with shorter relapse-free survival in patients with advanced stage (stage III/IV) ovarian carcinoma treated with platinum and taxane chemotherapy. Furthermore, overexpression of NAC-1 in primary tumors predicted recurrence within 6 months after primary cytoreductive surgery followed by standard platinum and taxane chemotherapy. NAC-1 expression levels were measured and compared among the human ovarian cancer cell line (KF28), cisplatin-resistant cell line (KFr13) induced from KF28, and paclitaxel-resistant cell lines (KF28TX and KFr13TX) induced by exposing KF28 and KFr13 to dose-escalating paclitaxel. Overexpression of NAC-1 was observed in only the Taxol-resistant KF28TX and KFr13 TX cells but not in KF28 or cisplatin-resistant KFr13 cells. To confirm that NAC-1 expression was related to Taxol resistance, we used two independent but complementary approaches. NAC-1 gene knockdown in both KF28TX and KFr13TX rescued paclitaxel sensitivity. Additionally, engineered expression of NAC-1 in RK3E cells induced paclitaxel resistance.


CONCLUSIONS
These results suggest that NAC-1 regulates Taxol resistance in ovarian cancer and may provide an effective target for chemotherapeutic intervention in Taxol-resistant tumors.
Ishibashi
Masako
M
Department of Obstetrics and Gynecology, Shimane University School of Medicine, Tohoku University, Sendai, Japan.
Nakayama
Kentaro
K
Yeasmin
Shamima
S
Katagiri
Atsuko
A
Iida
Kouji
K
Nakayama
Naomi
N
Fukumoto
Manabu
M
Miyazaki
Kohji
K
D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*; D017239:Paclitaxel / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D012189:Retrospective Studies
D000972:Antineoplastic Agents, Phytogenic; C516477:NACC1 protein, human; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D017239:Paclitaxel