Abstract
Ovarian cancer (OC) is highly resistant to current treatment strategies based on a combination of surgery, chemotherapy and radiation therapy. We have recently demonstrated the anti-neoplastic effect of Amla extract (Emblica officinalis, AE) on OC cells in vitro and in vivo. We hypothesized that AE attenuates growth of OC through microRNA (miR)-regulated mechanism(s). The inhibitory effect of AE on proliferation, migration and invasiveness (P≤0.001) of SKOV3 cells and >90% attenuation of tumor growth in a xenograft mouse model suggested multiple targets. RT-qPCR analysis of microRNAs associated with OC showed a >2,000-fold increase in the expression of miR-375 in AE-treated SKOV3 cells that was blocked by an exogenous miR-375 inhibitor (P≤0.001). AE also decreased the gene and protein expression of IGF1R, a target of miR-375 (P≤0.001), and SNAIL1 (P≤0.002), an EMT-associated transcription factor that represses E-cadherin expression (P≤0.003). AE increased E-cadherin expression (P≤0.001). Treatment of SKOV3 cells with AE resulted in increased miR-375 in exosomes in the medium (P≤0.01). Finally, AE significantly decreased the expression of IGF1R and SNAIL1 proteins during attenuation of SKOV3-derived xenograft tumor. Together, these results show that AE modulates cancer cells and the tumor microenvironment via activation of miR-375 and by targeting IGF1R and SNAIL1 in OC cells.
Highlights
Ovarian cancer (OC) is a leading cause of female mortality [1]
SKOV3 cells are a highly aggressive OC cell line and an anti-proliferative effect of Amla extract (AE) would provide strong validation of our previous observations based on using OVCAR3 cells [14]
Principal findings of these studies show that AE caused more than 2000-fold increase in miR375 expression and down regulated the expression of insulin-like growth factor 1 receptor (IGF1R) and SNAIL1 in OC cells
Summary
Ovarian cancer (OC) is a leading cause of female mortality [1]. Approximately 190,000 new cases of OC are diagnosed each year [2]. In United State approximately 22,000 women were diagnosed with OC, and 15,000 women died from OC in 2014 alone [1]. Diagnosis of OC is often missed and aggressive intervention at late stages is generally unsuccessful. Current treatment of OC relies on a combination of surgery, chemotherapy and radiation that yields poor results with a five year survival rate of about 30% [3]. Anticancer drugs are often highly toxic and contribute to morbidity and poor outcome [4]. There is an ongoing effort to identify novel therapeutic agents to target multiple cellular processes for a comprehensive inhibition of tumor growth and metastasis
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