Caudatin targets TNFAIP1/NF-κB and cytochrome c/caspase signaling to suppress tumor progression in human uterine cancer

Abstract

Caudatin, a C-21 steroidal glyco-side isolated from Chinese herbs, has a long history of use for the treatment of multiple diseases, including cancers. However, the precise mechanisms of actions of caudatin in human uterine cancer cells remain unclear. In this study, we investigated the molecular mechanisms by which caudatin inhibits cell growth in human cervical carcinoma cell line (HeLa) and endometrial carcinoma cell line (HEC-1A). Treatment with caudatin promoted cell morphology change, inhibited cell proliferation, colony formation, migration and spheroid formation, and induced cell apoptosis. Our results showed that the expression of tumor necrosis factor; α-induced protein 1 (TNFAIP1) was downregulated in uterine cancer cells and tissues compared to paired adjacent non-tumor uterine tissues. Further molecular mechanism study showed that caudatin can directly regulate TNFAIP1 expression in a concentration-dependent manner and also associated with the downregulation of NF-κB and upregulation of BAX/BcL-2 ratio and caspase-3. Moreover, we found that overexpression of TNFAIP1 inhibits the growth and invasion, and induces apoptosis in uterine cancer cells through inhibition of the NF-κB pathway, suggesting that TNFAIP1 may act as a potential therapeutic target for the treatment of cancer. We found that caudatin inhibited tumorigenicity and upregulated TNFAIP1 in vivo. Taken together, caudatin impacts on cell proliferation, migration and apoptosis of uterine cancer cells by regulating several carcinogenesis-related processes, including a novel mechanism involving the targeting of TNFAIP1/NF-κB signaling. Our findings provide new insights into understanding the anticancer mechanisms of caudatin in human uterine cancer therapy.

Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation

“…TNFAIP1 is induced by tumor necrosis factor alpha (TNFα) and interleukin-6 (IL6) and has roles in DNA synthesis, DNA repair, and apoptosis (Wolf et al, 1992). TNFAIP1 has tumor suppressive functions in several cancer types, including gastric cancer, NSCLC, pancreatic cancer, and uterine cancer, by supporting tumor growth through NFκB signaling (Cui et al, 2015; Tan et al, 2016; Zhang et al, 2015; Zhou et al, 2013). We propose that reduced NADPH levels upon genetic and pharmacological inhibition of IDH1 cooperates with increased NDUFS1, GNG4 and TNFAIP1 levels to inhibit proliferation and promote ROS-induced apoptosis.…”

Total C-21 steroidal glycosides, isolated from the root tuber of Cynanchum�auriculatum Royle ex Wight, attenuate hydrogen peroxide-induced oxidative injury and inflammation in L02 cells

“…TCSGs, the most important active components of Baishouwu, are commonly considered to be strong antioxidants due to their high free radical scavenging properties. Recent studies have revealed that TCSGs affect cellular inflammatory stress and inhibit tumors by regulating carcinogenesis-associated processes ( 3 , 9 , 10 , 39 ). In addition, it has been demonstrated that TCSGs exert hepatoprotective effects against liver injury induced by carbon tetrachloride in vivo ( 17 ).…”

Caudatin Isolated from Cynanchum auriculatum Inhibits Breast Cancer Stem Cell Formation via a GR/YAP Signaling

“…The isolated compound was identified as caudatin ( Figure 2). In a variety of cancer cells, caudatin suppresses proliferation and induces caspase-dependent apoptosis [12,47]. Our data showed that caudatin inhibited the proliferation of breast cancer cells and the growth of mammospheres.…”

“…It has been reported that caudatin induces cancer cell apoptosis through C/EBP Homologous Protein (CHOP)-, p38-mitogen-activated protein kinase (MAPK)-, and c-Jun N-terminal kinase (JNK)-mediated upregulation of death receptor 5 expression [11]. Furthermore, caudatin suppresses uterine cancer cells by regulating α-induced protein 1 (TNFAIP1)/Nuclear factor-κB (NF-κB) signaling [12]. Although evidence of the anticancer effects of caudatin is expanding, there is no report concerning the mechanisms underlying the effects of caudatin on breast cancer stem cells (BCSCs).…”