Abstract
BackgroundBreast cancer is the most prevalent cancer among women worldwide. WZ35, an analog of curcumin, has been demonstrated to remarkably improve the pharmacokinetic profiles in vivo compared with curcumin. WZ35 exhibits promising antitumor activity in gastric cancer, HCC, colon cancer. However, antitumor effects of WZ35 in breast cancer and its underlying molecular mechanisms remain unclear.MethodsCCK8, Flow cytometry and transwell assays were used to measure cell proliferation, cell cycle arrest, apoptosis, cell migration and invasion. We constructed xenograft mouse model and lung metastasis model to assess the antitumor activities of WZ35 in vivo. To explore the underlying molecular mechanisms of WZ35, we performed a series of overexpression and knockdown experiments. The cellular oxygen consumption rates (OCRs) was measured to assess mitochondrial dysfunction.ResultsWe found that treatment of breast cancer cells with WZ35 exerts stronger anti-tumor activities than curcumin both in vitro and in vivo. Mechanistically, our research showed that WZ35 induced reactive oxygen species (ROS) generation and subsequent YAP mediated JNK activation in breast cancer cells. Abrogation of ROS production markedly attenuated WZ35 induced anti-tumor activities as well as YAP and JNK activation. In addition, ROS mediated YAP and JNK activation induced mitochondrial dysfunction in breast cancer cells.ConclusionOur study showed that novel anti-cancer mechanisms of WZ35 in breast cancer cells and ROS-YAP-JNK pathway might be a potential therapeutic target for the treatment of breast cancer patients.
Highlights
Breast cancer is the most prevalent cancer among women worldwide
WZ35 exhibits stronger anti-tumor activities than curcumin in the breast cancer cells We firstly evaluated the effects of WZ35 on the proliferation of breast cancer cell lines, Hs578T and MDA-MB-231 by using CCK8 assay
(See figure on previous page.) Fig. 2 WZ35 inhibits MDA-MB-231 xenograft tumor growth and metastasis in vivo. a A growth curve analysis of the tumor growth in curcumin, WZ35 or Castor oil treated groups. b Expression of ki67 in tumor tissues was determined by immunohistochemistry. c Mice body weight was measured during the 17-day treatment of WZ35 and curcumin. d Representative microscopic images of lung metastatic lesions at 21 days after treatment of mice with curcumin or WZ35 (0.2 mL, 25 mg/kg for each). e The number of lung metastatic tumors was calculated. f Immunofluorescence were used to test the expression level of E-cadherin, N-cadherin, Matrix Metalloproteinase-2 (MMP-2) and Matrix Metalloproteinase-9 (MMP-9) from curcumin, WZ35, Vehicle and control group
Summary
Breast cancer is the most prevalent cancer among women worldwide. WZ35 exhibits promising antitumor activity in gastric cancer, HCC, colon cancer. Antitumor effects of WZ35 in breast cancer and its underlying molecular mechanisms remain unclear. Poor bioavailability in vivo of curcumin per se has impeded its use in cancer therapy [11, 12]. To solve this problem, a new compound of curcumin analog WZ35, 1-(4-hydroxy-3-methoxyphenyl)-5-(2-nitrophenyl) penta-1,4-dien − 3-one, has been designed and synthesized by our lab. Similar anti-cancer effects have been found in colon cancer and hepatocellular carcinoma (HCC) [14, 15]. Hyperactivation of YAP is associated with a better prognosis in breast cancer patients, which suggests that YAP might act as a tumor suppressor in breast cancer [20]
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