Chinese Propolis Exerts Anti-Proliferation Effects in Human Melanoma Cells by Targeting NLRP1 Inflammatory Pathway, Inducing Apoptosis, Cell Cycle Arrest, and Autophagy.

Yufei Zheng,Xiasen Jiang,Kai Wang,Kai Wang,Fuliang Hu,Xi Chen,Yuqi Wu

doi:10.3390/nu10091170

Abstract

Melanoma is a malignant tumor that begins in the melanocyte and has the highest mortality rate among all cutaneous tumors. Chinese propolis (CP) has been shown to have a potent antitumor effect against various cancers. In this study, we uncovered the combined effects of antiproliferation and anti-inflammation of CP on suppressing the progression of human melanoma cell line A375. We evaluated the alterations of protein expression after CP treatment by Western blot. After CP treatment, A375 cells underwent intrinsic apoptosis and cell cycle arrest. Furthermore, we found that CP suppressed inflammation in A375 cells. NLRP1 (NLR family pyrin domain containing 1), confirmed as a proinflammatory protein in melanoma progression, was downregulated significantly by CP, as were the NLRP1-related caspase activation and recruitment domains (CARD) proteins, including caspase-1 and caspase-4. Additionally, decreasing mRNA levels of IL-1α, IL-1β, and IL-18 further proved the negative regulation of CP on the melanoma inflammatory environment. We also discovered that CP induced autophagy in A375 cells. Interestingly, inhibiting autophagy in CP-treated cells diminished its antitumor effect, suggesting that the autophagy was attributed to CP-induced apoptosis. Collectively, CP is a promising candidate for drug development for melanoma therapy.

Highlights

Melanoma is the most rapidly increasing malignant skin disease, and is characterized by high lethality and frequent metastasis [1,2]
Our previous study determined that pinocembrin has an antitumor effect on melanoma progression [38], and Pichichero et al have proved that chrysin can inhibit melanoma proliferation in vitro [42]
We found that caspase-2 was activated along with a decreased level of its full-length form after Chinese propolis (CP) treatment, indicating that the intrinsic apoptosis induced by CP may partly be ascribed to the suppression of NLRP1 and the subsequent regulation of caspase-1, as well as caspase-2

Summary

Introduction

Melanoma is the most rapidly increasing malignant skin disease, and is characterized by high lethality and frequent metastasis [1,2]. According to a WHO report, there were 3.1 million new diagnoses of melanoma and 59,800 deaths due to the disease worldwide in 2015 [4]. Reactive oxygen species (ROS), damaged DNA and altered cell homeostasis are known to interact with inflammasomes [5,6]. Following stimulation, such as UV light, keratinocytes, melanocytes, and Langerhans cells will secrete pro-inflammatory cytokines which build an inflammatory microenvironment allowing tumorigenesis and metastasis [7]. Like IL-6, TNF-α, IFN-γ, IL-10, and TGF-β1, have been reported to play a role in the progression and immunosurveillance

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Conclusion