ABTB/POZGene,NAC-1, a Tumor Recurrence–Associated Gene, as a Potential Target for Taxol Resistance in Ovarian Cancer

Abstract

Purpose: 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-1expression and ovarian cancer. Experimental Design: NAC-1expression 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-1function inTaxol 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-1was observed in only theTaxol-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-1in 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 inTaxol-resistant tumors.

Biological and clinical significance of NAC1 expression in cervical carcinomas: a comparative study between squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas

“…The mechanism underlying the association between NAC1 expression and shorter survival is not known; however, because mortality of patients with cervical carcinoma is directly related to the recurrence of disease after radiotherapy, it is conceivable that NAC1 expression may confer resistance to radiotherapy and/or enhance cell proliferation in radioresistant recurrent tumors. Recently, we reported that NAC1 was related to paclitaxel resistance in ovarian carcinomas [16,17]. The current findings of a positive relationship between NAC1 expression and adverse patient outcome may be explained by our previous findings.…”

“…The levels of NAC1 expression correlate with tumor recurrence in ovarian serous carcinomas, and intense NAC1 immunoreactivity in primary ovarian tumors predicts early recurrence [13,16]. In addition, NAC1 expression is related to taxane resistance in advancedstaged ovarian carcinomas [16,17]. Recently, we have reported that NAC1 expression is more common in cervical adenocarcinomas/adenosquamous carcinomas than in cervical squamous cell carcinomas and that NAC1 expression correlates with a worse prognosis in patients with squamous cell carcinomas of uterine cervix [15].…”

“…NAC1 is a transcription repressor that is involved in self-renewal and the maintenance of pluripotency in embryonic stem cells [14]. NAC1 is significantly overexpressed in several types of human carcinomas [13,15,16]. The levels of NAC1 expression correlate with tumor recurrence in ovarian serous carcinomas, and intense NAC1 immunoreactivity in primary ovarian tumors predicts early recurrence [13,16].…”

“…NAC1 is significantly overexpressed in several types of human carcinomas [13,15,16]. The levels of NAC1 expression correlate with tumor recurrence in ovarian serous carcinomas, and intense NAC1 immunoreactivity in primary ovarian tumors predicts early recurrence [13,16]. In addition, NAC1 expression is related to taxane resistance in advancedstaged ovarian carcinomas [16,17].…”

NAC1, a potential stem cell pluripotency factor expression in normal endometrium, endometrial hyperplasia and endometrial carcinoma

“…NAC1 is a transcription repressor that is involved in self renewal and the maintenance of pluripotency in embryonic stem cells (18). NAC1 is significantly overexpressed in several types of human carcinomas (17), where it plays a critical role in maintaining tumor cell proliferation and survival (17,(19)(20)(21). Recently, we showed that NAC1 is essential for the proliferation of normal cyclic endometrial glandular cells and is up-regulated by estrogen (22).…”