Sphingosine kinase 2 (Sphk2) has an oncogenic role in cancer. A recently developed first-in-class Sphk2 specific inhibitor ABC294640 displays antitumor activity in many cancer models. However, the role of Sphk2 and the antitumor activity of its inhibitor ABC294640 are not known in cholangiocarcinoma. We investigated the potential of targeting Sphk2 for the treatment of cholangiocarcinoma. We found that Sphk2 is overexpressed in five established human cholangiocarcinoma cell lines (WITT, HuCCT1, EGI-1, OZ and HuH28) and a new patient-derived cholangiocarcinoma cell line (LIV27) compared to H69 normal cholangiocytes. Inhibition of Sphk2 by ABC294640 inhibited proliferation and induced caspase-dependent apoptosis. Furthermore, we found that ABC294640 inhibited STAT3 phosphorylation, one of the key signaling pathways regulating cholangiocarcinoma cell proliferation and survival. ABC294640 also induced autophagy. Inhibition of autophagy by bafilomycin A1 or chloroquine potentiated ABC294640-induced cytotoxicity and apoptosis. In addition, ABC294640 in combination with sorafenib synergistically inhibited cell proliferation of cholangiocarcinoma cells. Strong decreases in STAT3 phosphorylation were observed in WITT and HuCCT1 cells exposed to the ABC294640 and sorafenib combination. These findings provide novel evidence that Sphk2 may be a rational therapeutic target in cholangiocarcinoma. Combinations of ABC294640 with sorafenib and/or autophagy inhibitors may provide novel strategies for the treatment of cholangiocarcinoma.
BACKGROUND Recent trends toward urbanization in developing countries like Ghana, coupled with nutritional transition and aging populations, have led to a rapid increase in noncommunicable diseases like obesity, diabetes, and hypertension. The purpose of this study was to evaluate the association between socioeconomic status and cardiometabolic risk factors among women in Ghana. METHODS Data for this analysis were obtained from Wave 1 of the Ghana Study of Global Aging and Health, conducted in 2007, and included women 18 years and older. Survey weighted descriptive and multivariable linear regression models were used to examine the association between socioeconomic status and cardiometabolic risk factors. RESULTS Among a total of 1988 women, 48% were 40–64 years old. Almost half of the participants were overweight or obese (47%) and 21% had current hypertension, whereas only 4.3% and 2% of women self-reported a history of hypertension and diabetes, respectively. Adjusted analysis indicated that women with a high school education had 2-fold increased odds of being overweight or obese compared with those with no formal education (odds ratio [OR]: 2.02, 95% confidence interval [CI]: 1.20–3.42). Women employed in the public sector had almost a 5 times higher odds of being overweight or obese (OR: 4.94, 95% CI: 1.42–17.15), whereas those employed in the private sector or self-employed had reduced odds of diabetes (OR: 0.27, 95% CI: 0.10–0.70) and hypertension (OR: 0.43, 95% CI: 0.21–0.86). CONCLUSION The prevalence of cardiometabolic risk factors varies by socioeconomic status among Ghanaian women. Targeted intervention programs to reduce overweight and obesity may begin among Ghanaian women employed in the public sector, and improved access to health care will be critical for timely diagnosis and management of other chronic disease risk factors.
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