Anesthetic propofol epigenetically regulates breast cancer trastuzumab resistance through IL-6/miR-149-5p axis

Dan Tian,Miao Tian,Zhi-Ming Ma,Jin-Long Li,Yun-Feng Cui,Lei-Lei Zhang

doi:10.1038/s41598-020-65649-y

Dan Tian, Miao Tian + Show 4 more

Open Access

https://doi.org/10.1038/s41598-020-65649-y

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Abstract

Propofol, a common intravenous anesthetic, has been found to exert anti-cancer effects with inhibition of cancer cell proliferation, migration and invasion. We tested its possible action against HER2-overexpressing breast cancer cells that developed resistance against trastuzumab. Cell viability assay, ELISA for cytokines, mammosphere formation, quantitative RT-PCR for EMT/IL-6-targeting miRNAs and the in vivo experimental pulmonary metastasis model were performed to understand the epigenetic action of propofol. Propofol sensitized HER2 overexpressing cells to trastuzumab but such action was even more pronounced in resistant cells. Increased cytokines IL-6 as well as IL-8 were released by resistant cells, along with increased mammospheres and induction of EMT, all of which was inhibited by propofol. IL-6 targeting tumor suppressor miR-149-5p was found to be the novel miRNA that was up-regulated by propofol, resulting in the observed effects on cell viability, IL-6 production, mammospheres generation as well as EMT induction. Further, antagonizing miR-149-5p attenuated the propofol effects confirming the epigenetic activity of propofol through miR-149-5p regulation. Finally, in vivo validation in an experimental metastasis model conformed an inhibitory action of propofol against experimental lung metastasis and the essential mechanistic role of miR-149-5p/IL-6 loop. These results present a novel role of general anesthetic propofol against resistant breast cancer cells and the underlying epigenetic regulation of a tumor suppressor miRNA.

Highlights

Propofol is a commonly used general anesthetic[1]
We chose the HER2 overexpressing SKBR3 breast cancer cells, exposed them to trastuzumab for prolonged time to generate trastuzumab resistance (Tr-R) SKBR3 cells and studied the action of propofol against these cells, along with mechanistic insights
With the goal to check the effect of propofol on trastuzumab resistance of HER2 overexpressing breast cancer cells, we subjected the HER2 overexpressing SKBR3 cells to increasing doses of trastuzumab in the presence and absence of propofol

Summary

Introduction

Propofol is a commonly used general anesthetic[1] It is used for induction as well as maintenance of anesthesia. Even though the clinical studies have provided contrary conclusions, with some supporting benefit while others finding no survival benefit associated with the use of propofol as the anesthetic of choice during cancer surgeries[4,5,6,7], the in vitro data supporting a role of propofol against proliferation, invasion etc. Propofol is effective with demonstrated role in preventing proliferation[10], inducing apoptosis[11] and reducing metastasis[12]. We chose the HER2 overexpressing SKBR3 breast cancer cells, exposed them to trastuzumab for prolonged time to generate Tr-R SKBR3 cells and studied the action of propofol against these cells, along with mechanistic insights. In addition to cell line-based studies, we confirmed the mechanism in vivo in an experimental pulmonary metastasis model

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