Objective： Yes Associated Protein （YAP） is a downstream effector that negatively regulated by Hippo kinase LATS1/2. As a transcriptional coactivator, YAP controls the transactivation of variety target genes to prom...Objective： Yes Associated Protein （YAP） is a downstream effector that negatively regulated by Hippo kinase LATS1/2. As a transcriptional coactivator, YAP controls the transactivation of variety target genes to promote cell proliferation which is a critical survival input for cancer cells, thus the inhibition of YAP function is a promising strategy to treat cancer patients. The aim of this study was to explore YAP inhibitors derived from natural products using a cell-based YAP-TEADs luciferase reporter assay and investigate the functional activities of the novel inhibitor. Methods： natural compounds were used by 8×GTIIC luciferase reporter assay to screen YAP inhibitor. Phosphorylation of YAP and AMPK were detected by Western Blotting. The target genes of YAP were determined through RT-PCR. Inhibition on HepG2 cells of screened compounds were assessed by the Sulforhodamine B （SRB） assay. Results： we found that Shikonin （derived from the traditional Chinese medical herb Zicao （Lithospermum erythrorhizon）） exerted significant suppression against the transcriptional activity of YAP （inhibition ratio=74.3%）, accompanied with increased phosphorylation of YAP protein upon within short-exposure to cancer cells. Shikonin treated on HepG2 induced phosphorylation of AMPK. In HepG2 cell lines, Shikonin exhibited a profound cytotoxicity in a concentration manner. Conclusion： our results indicated that the inhibition activity of Shikonin on YAP function was probably due to the activation of AMPK by phosphorylation. Moreover, Shikonin exhibited potent cytotoxicity on cancer cells. In summary, the present study identifies Shikonin as a novel natural inhibitor of YAP function and could be an anti-cancer drug candidate for cancer treatment.展开更多
Dear Editor,Targeting PI3K is a promising approach for cancer therapy,and the PI3Kα-selective inhibitor alpelisib has been approved for breast cancer treatment.1,2,3 However,the development of acquired resistance pos...Dear Editor,Targeting PI3K is a promising approach for cancer therapy,and the PI3Kα-selective inhibitor alpelisib has been approved for breast cancer treatment.1,2,3 However,the development of acquired resistance poses a significant clinical challenge.Loss of PTEN and activation of mTOR,CDK4/6,or PIM have been reported to mediate acquired resistance to alpelisib.4,5,6,7 The mechanisms leading to resistance to PI3Kαinhibitors appear to be different under different circumstances,and the aforementioned strategies may be beneficial for a particular group of patients.New strategies to overcome acquired resistance in a broad spectrum of patients need to be discovered.展开更多
Hepatocellular carcinoma (HCC) is one of the most rapidly growing and prevalent cancers in the whole world. The characterized hypoxia region inside the HCC tumors has been recently found as the key driver of HCC malig...Hepatocellular carcinoma (HCC) is one of the most rapidly growing and prevalent cancers in the whole world. The characterized hypoxia region inside the HCC tumors has been recently found as the key driver of HCC malignance and treatment failure, leading to a variety of hypoxia-related biological consequences including angiogenesis, metastasis, metabolism deregulation and drug resistance, which ultimately resulted in treatment failure of HCC. This review will summarize the signaling pathways involved in hypoxia-mediated malignance of HCC and discuss current advances of hypoxia-targeted therapies.展开更多
基金This work was supported National Key R＆D Program of China （No. 2017YFE0102200）, National Natural Science Foundation for Distinguished Young Scholar of China （81625024） and National Natural Science Foundation of China （81773753） to B. Yang.
文摘Objective： Yes Associated Protein （YAP） is a downstream effector that negatively regulated by Hippo kinase LATS1/2. As a transcriptional coactivator, YAP controls the transactivation of variety target genes to promote cell proliferation which is a critical survival input for cancer cells, thus the inhibition of YAP function is a promising strategy to treat cancer patients. The aim of this study was to explore YAP inhibitors derived from natural products using a cell-based YAP-TEADs luciferase reporter assay and investigate the functional activities of the novel inhibitor. Methods： natural compounds were used by 8×GTIIC luciferase reporter assay to screen YAP inhibitor. Phosphorylation of YAP and AMPK were detected by Western Blotting. The target genes of YAP were determined through RT-PCR. Inhibition on HepG2 cells of screened compounds were assessed by the Sulforhodamine B （SRB） assay. Results： we found that Shikonin （derived from the traditional Chinese medical herb Zicao （Lithospermum erythrorhizon）） exerted significant suppression against the transcriptional activity of YAP （inhibition ratio=74.3%）, accompanied with increased phosphorylation of YAP protein upon within short-exposure to cancer cells. Shikonin treated on HepG2 induced phosphorylation of AMPK. In HepG2 cell lines, Shikonin exhibited a profound cytotoxicity in a concentration manner. Conclusion： our results indicated that the inhibition activity of Shikonin on YAP function was probably due to the activation of AMPK by phosphorylation. Moreover, Shikonin exhibited potent cytotoxicity on cancer cells. In summary, the present study identifies Shikonin as a novel natural inhibitor of YAP function and could be an anti-cancer drug candidate for cancer treatment.
文摘Dear Editor,Targeting PI3K is a promising approach for cancer therapy,and the PI3Kα-selective inhibitor alpelisib has been approved for breast cancer treatment.1,2,3 However,the development of acquired resistance poses a significant clinical challenge.Loss of PTEN and activation of mTOR,CDK4/6,or PIM have been reported to mediate acquired resistance to alpelisib.4,5,6,7 The mechanisms leading to resistance to PI3Kαinhibitors appear to be different under different circumstances,and the aforementioned strategies may be beneficial for a particular group of patients.New strategies to overcome acquired resistance in a broad spectrum of patients need to be discovered.
基金the National Natural Science Foundation for Distinguished Young Scholar of China(81625024).
文摘Hepatocellular carcinoma (HCC) is one of the most rapidly growing and prevalent cancers in the whole world. The characterized hypoxia region inside the HCC tumors has been recently found as the key driver of HCC malignance and treatment failure, leading to a variety of hypoxia-related biological consequences including angiogenesis, metastasis, metabolism deregulation and drug resistance, which ultimately resulted in treatment failure of HCC. This review will summarize the signaling pathways involved in hypoxia-mediated malignance of HCC and discuss current advances of hypoxia-targeted therapies.
