Abstract
We have previously demonstrated that carnosol, a naturally occurring diterpene, inhibited in vitro cell viability and colony growth, as well as induced cell cycle arrest, autophagy and apoptosis in human triple negative breast cancer (TNBC) cells. In the present study, we evaluated the ability of carnosol to inhibit tumor growth and metastasis in vivo. We found that non-cytotoxic concentrations of carnosol inhibited the migration and invasion of MDA-MB-231 cells in wound healing and matrigel invasion assays. Furthermore, gelatin zymography, ELISA, and RT-PCR assays revealed that carnosol inhibited the activity and downregulation the expression of MMP-9. Mechanistically, we demonstrated that carnosol suppressed the activation of STAT3 signaling pathway through a ROS-dependent targeting of STAT3 to proteasome-degradation in breast cancer cells (MDA-MB-231, Hs578T, MCF-7, and T47D). We show that blockade of proteasome activity, by MG-132 and bortezomib, or ROS accumulation, by N-acetylcysteine (NAC), restored the level of STAT3 protein. In addition, using chick embryo tumor growth assay, we showed that carnosol significantly and markedly suppressed tumor growth and metastasis of breast cancer xenografts. To the best of our knowledge, this is the first report which shows that carnosol specifically targets signal transducer and activator of transcription 3 (STAT3) for proteasome degradation in breast cancer. Our study further provide evidence that carnosol may represent a promising therapeutic candidate that canmodulate breast cancer growth and metastasis.
Highlights
Breast cancer still represents the most common cancers as well as one of the leading causes of world-wide cancer-related mortality; it accounted for 2.09 million cases and 627,000 cancer-related deaths in 2018 [1]
We have examined the effect of proteasome inhibitor on signal transducer and activator of transcription 3 (STAT3) in another triple negative breast cancer (TNBC) cell line, namely Hs578T
The aim of this study was to investigate the efficacy of carnosol to inhibit breast cancer tumor growth and metastasis in vivo
Summary
Breast cancer still represents the most common cancers as well as one of the leading causes of world-wide cancer-related mortality; it accounted for 2.09 million cases and 627,000 cancer-related deaths in 2018 [1]. TNBC represents a heterogeneous subtype of breast cancers that belongs mainly to the basal-like breast cancers and is associated with aggressive clinical conditions, where targeted therapies are currently limited [2]. TNBC is a diagnosis of exclusion since those cells are known to lack the expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor [3]. Breast cancer therapies have witnessed enormous developments in recent years, no highly efficient anti-cancer treatment has been discovered. This might be due to the lack of complete understanding of the etiological factors underlying carcinogenesis, local invasiveness and distant metastasis. Identification of novel drugs that targets TNBC are increasingly needed
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