Abstract
Studies have investigated the tumor suppressive role of rottlerin in carcinogenesis. However, the molecular mechanisms of rottlerin-induced anti-tumor activity are largely unclear. Skp2 (S-phase kinase associated protein 2) has been validated to play an oncogenic role in a variety of human malignancies. Therefore, inactivation of Skp2 could be helpful for the treatment of human cancers. In the current study, we explore whether rottlerin could inhibit Skp2 expression, leading to inhibition of cell growth, migration and invasion in breast cancer cells. We found that rottlerin treatment inhibited cell growth, induced apoptosis and cell cycle arrest. We also revealed that rottlerin suppressed cell migration and invasion in breast cancer cells. Mechanically, we observed that rottlerin significantly down-regulated the expression of Skp2 in breast cancer cells. Importantly, overexpression of Skp2 abrogated rottlerin-mediated tumor suppressive activity, whereas down-regulation of Skp2 enhanced rottlerin-triggered anti-tumor function. Strikingly, we identified that rottlerin exhibited its anti-tumor potential partly through inactivation of Skp2 in breast cancer. Our findings indicate that rottlerin could be a potential safe agent for the treatment of breast cancer.
Highlights
Breast cancer is one of the common diagnosed malignancies and the main cause of cancer mortality among females worldwide [1]
To determine whether rottlerin suppresses cell proliferation, we performed CellTiterGlo® luminescence (CTG) assay in MCF-7 and MDA-MB-231 cells after different concentrations of rottlerin treatment for 48 hours and 72 hours, respectively
Accumulated evidence has revealed that Skp2 plays an oncogenic role in tumorigenesis [19, 20]
Summary
Breast cancer is one of the common diagnosed malignancies and the main cause of cancer mortality among females worldwide [1]. In the United States, approximately 246,660 new breast cancer cases were occurred in female in 2016, and 40,450 Americans will die from this disease [2]. Some signaling pathways have been identified to play an oncogenic role in the development and progression of breast cancer. Akt, mTOR (mammalian target of rapamycin), MAPK (mitogen-activated protein kinases), NF-κB (nuclear factor-κB), Notch, SHH (sonic hedgehog) pathways have been validated to be positively associated with breast tumorigenesis [3,4,5,6]. Skp exerts its oncogenic function through targeting its substrates [10]. Skp has been revealed to critically enhance the pathogenesis of breast cancer [3]. Due to its oncogenic role in tumorigenesis, inhibition of Skp could be a promising therapeutic strategy for combating breast cancer
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