Orbifloxacin br Nanog Klf and Oct and
Nanog, Klf4, and Oct4, and downregulation the portion of the CD44highCD24low cell population.
Ovarian cancer is an irreversible malignant tumor with high mor-tality (Siegel et al., 2014). The current therapeutic strategies including surgical resection, radiotherapy and chemotherapy, have improved continuously in recent years, but the survival rates of ovarian cancer have only increased slightly. The main reason is that ovarian cancer is a highly heterogeneous disease and blocking a single pathway creates feedback and simultaneous activation of a wide range of interactive and/or redundant pathways. Therefore, new therapeutic targets are urgently needed. In the previous studies, Pin1 was found to be promi-nently overexpressed, and inversely correlated with disease progression
in ovarian cancer (Beretta et al., 2016; Lu and Hunter, 2014; Russo Spena et al., 2018). Pin1 inhibition causes the collapse of numerous oncogenic pathways at the same time, so targeting Pin1 is advantageous as a cancer therapy (Luo et al., 2009). Our results demonstrated that celastrol suppressed Pin1 expression in dose-dependent manner and revealed that Pin1 inhibitors oﬀer a novel approach to enhance the therapeutic eﬃcacy of celastrol against ovarian cancer.
The cancer stem cells (CSC) can self-renew, diﬀerentiate, initiate and sustain tumor growth, and are the major reason for cancer recur-rence and metastasis. Therefore, these cells may be a better target for therapeutic agents used to treat ovarian cancer. The eﬀect of celastrol on CSC has not been reported before. The expression of CD44 is used as a prognostic indicator for decreased survival time and promotes the development of carboplatin resistance and metastasis in ovarian cancer
(Karan Krizanac et al., 2018). The CD44highCD24low of ovarian cancer cells that displayed diﬀerentiation potential, drug resistance and high invasion can be a CSC marker (Meng et al., 2012). Our study demon-
strated that celastrol could inhibit the expression of stem cell marker CD44 and downregulate the portion of CD44highCD24low cell population
in SKOV3 cells. Meanwhile, the stem cell markers Nanog, Klf4, and Oct4 also decreased in celastrol treated cells. It revealed that celastrol has potential for development of novel chemotherapeutic agents for treatment of malignant cancers, especially against CSC.
Pin1 is important in the Orbifloxacin and can also regulate the ex-pression of cycle regulator, Cyclin D1, CDK2, CDK4, CDK6 and P53 (Lin et al., 2015). Our results demonstrated that celastrol depressed the expression of the Cyclin D1, CDK2, and CDK4, which suggests that celastrol induced cell cycle arrest through its eﬀects on the expression
Fig. 7. A proposed schema of the potential mechanism of action of celastrol on ovarian cancer.
of Pin1. Pin1 can increase the expression of Bcl-2 (a critical suppressor of apoptosis) and decrease the expression of Bax, a proapoptotic reg-ulator (Lv et al., 2010). Celastrol can suppress Bcl-2 expression while increasing Bax expression in ovarian cancer, which suggests that ce-lastrol induced apoptosis through its eﬀects on the expression of Pin1. It has been reported that Pin1 activates the expression of IL-6/STAT3, NF-κB, JNK/P38 and Akt, which have a pivotal role in the maintenance of ovarian and other cancer stem cells (Akiyama et al., 2011; Atkinson et al., 2009; Choi et al., 2015; Korkaya et al., 2012; Liao et al., 2009; Liu et al., 2017; Lv et al., 2013; Marotta et al., 2011; Matsumoto et al., 2018; Seino et al., 2014). Our results show that celastrol suppresses the expression of IL-6/STAT3, NF-κB, JNK/P38 and Akt, which suggests that celastrol suppressed the stem cell properties through its eﬀect on the expression of Pin1. Therefore, the potent anticancer activity of ce-lastrol maybe closely related to Pin1 inhibition. r> Pin1 is an attractive drug target, as it is linked to the control of dozens of oncogenes and tumor suppressors and suppressing CSC properties. We intend to further validate these findings in vivo as well as to make additional structural modifications to improve the ability to target Pin1 and track the anti-cancer eﬀect of future treatments. We anticipate that celastrol may serve as a useful lead compound for the further development of highly potent inhibitors of Pin1 for the treat-ment of ovarian cancer.
In conclusion, our studies provide strong evidence that celastrol inhibits cancer cell proliferation and migration, induces apoptosis and cell cycle arrest and restrains the cancer stem cell properties through suppression of Pin1 in ovarian cancer cells, as shown by the model proposed in Fig. 7. Pin1 may be a novel target for ovarian cancer and celastrol can be a lead compound to design inhibitors targeting Pin1.