Curcumol inhibits the expression of programmed cell death-ligand 1 through crosstalk between hypoxia-inducible factor-1α and STAT3 (T705) signaling pathways in hepatic cancer

doi:10.1016/j.jep.2020.112835

Journal of Ethnopharmacology

Volume 257, 15 July 2020, 112835

https://doi.org/10.1016/j.jep.2020.112835 Get rights and content

Highlights

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Curcumol inhibits HIF-1α protein synthesis and STAT3 activation.
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Curcumol inhibits the expression of PD-L1 by crosstalk between STAT3 and HIF-1α.
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Curcumol inhibits cell proliferation and angiogenesis by suppressing PD-L1.
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Curcumol restores the tumor-killing activity of T-cells by inhibition of PD-L1.
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Curcumol inhibits the growth of Hep3B cells in a xenograft tumor model.

Abstract

Ethnopharmacological relevance

Curcuma wenyujin is a Chinese traditional herbal medicine that is commonly used as an anti-oxidant, anti-proliferative, and anti-tumorigenic agent. Curcumol is a representative index component for the quality control of the essential oil of Curcuma wenyujin, which is currently used as an anti-cancer drug, and is included in the State Pharmacopoeia Commission of the People's Republic of China (2005). However, the mechanisms of action and molecular functions of curcumol are not yet fully elucidated.

Aim of the study

This study aimed to identify new effects of curcumol from the perspective of cancer immunotherapy.

Materials and methods

The underlying mechanism of the inhibition of programmed cell death-ligand 1 (PD-L1) activation by curcumol was investigated in vitro via homology modeling, molecular docking experiments, luciferase reporter assays, MTT assays, RT-PCR, western blotting, and immunofluorescence assays. Changes in cellular proliferation, angiogenesis, and the tumor-killing activity of T-cells were analyzed via EdU labeling, colony formation, flow cytometry, wound-healing, Matrigel Transwell invasion, tube formation, and T-cell killing. The anti-tumor activity of curcumol was assessed in vivo in a murine xenograft model using Hep3B cells.

Results

Curcumol reduced the expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) via JAK1, JAK2, and Src pathways and inhibited hypoxia-inducible factor-1α (HIF-1α) protein synthesis via mTOR/p70S6K/eIF4E and MAPK pathways. Furthermore, we revealed crosstalk between STAT3 and HIF-1α pathways, which collaboratively regulated PD-L1 activation, and that curcumol played a role in this regulation. Curcumol inhibited cell proliferation, S-phase progression, tube formation, invasion, and metastasis by inhibiting PD-L1. In addition, curcumol restored the activity of cytotoxic T-cells and their capacity for tumor cell killing by inhibiting PD-L1. In vivo experiments confirmed that curcumol inhibited tumor growth in a xenograft model.

Conclusions

These results illustrated that curcumol inhibits the expression of PD-L1 through crosstalk between HIF-1α and p-STAT3 (T705) signaling pathways in hepatic cancer. Thus, curcumol might represent a promising lead compound for the development of new targeted anti-cancer therapeutics.

Graphical abstract

Introduction

Curcuma wenyujin is a plant belonging to the family Zingiberaceae that is found in South Asia and China. It is used as a plant medicine based on its traditional effect to treat liver diseases and blood clots, and it is also prescribed as an analgesic. Curcuma wenyujin possesses anti-oxidant, anti-proliferative, and anti-tumorigenic properties, and many researchers demonstrated the efficacy of C (Liu et al., 2019). Curcuma wenyujin against various types of cancer include liver cancer (Liu et al., 2017). Curcuma wenyujin as a traditional Chinese medicine has been applied for medicinal purposes with its own unique theoretical system, which includes processing theory, technology, and standards, since ancient times (Liu et al., 2017). Curcuma wenyujin processed using vinegar has been applied in the clinic for 1500 years, beginning during the Northern and Southern dynasties (Chinese Pharmacopoeia). Curcumol is a representative index component for the quality control of the essential oil of Curcuma wenyujin, which is currently used as an anti-cancer drug, and is included in the State Pharmacopoeia Commission of the People's Republic of China (2005). Pharmacological studies suggested that curcumol has anti-tumor (Wei et al., 2019), anti-fibrotic (Jia et al., 2018), and anti-microbial (Chen et al., 2018) activities. Despite its known anti-cancer properties, the mechanisms of action and molecular effects of curcumol have not yet been fully elucidated. Therefore, from the perspective of cancer immunotherapy, it is particularly important to explore new effects of curcumol.

During the process of immune editing, cancer cells cleverly escape immune surveillance by manipulating immune checkpoint molecules, that are critical for maintaining balanced immune activity to prevent autoimmunity and limit collateral tissue damage (Watanabe and Nakajima, 2012). PD-L1 is a critical immune checkpoint molecule exploited by cancer cells to escape immune surveillance (Pardoll, 2012). When PD-L1 expressed on cancer cells and macrophages binds to programmed cell death protein-1 (PD-1) on activated cytotoxic T-cells infiltrating into tumors, the PD-L1–induced inhibitory signal blocks the anti-tumor activity of the cells. (Chen, 2004). However, interactions between PD-1 and PD-Ls are reversible, and blockade of PD-1/PD-L1 interactions restores effector T-cell functions and anti-tumor immune responses in vivo (Iwai et al., 2002; Koh et al., 2016). These findings suggest that blockade of the PD-1/PD-L1 pathway might affect immune-mediated tumor surveillance in vivo, thereby enhancing tumor cell death. Thus, the PD-1 and PD-L1 axis is recognized as an attractive target for cancer immunotherapy.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays a pivotal role in tumor cell proliferation, being constitutively activated (phosphorylated) in numerous cancer cells (Yu et al., 2009). STAT3 is phosphorylated by JAKs and c-Src kinase (Lee et al., 2015; Ren and Schaefer, 2002; Schreiner et al., 2002). STAT3 has two important phosphorylation sites for its activation, namely Tyr705 and Ser727. (Aggarwal et al., 2009). In cancer cells, STAT3 is activated via phosphorylation at Tyr705, leading to STAT3 dimerization and DNA binding, and phosphorylation of STAT3 at Ser727 enhances its homodimerization and DNA binding by facilitating the recruitment of p300/CBP. Following phosphorylation, the target genes of STAT3 include PD-L1. (Ihle, 1996; Koh et al., 2016; Lee et al., 2015).

Tumor hypoxia activates a battery of genes that induce angiogenesis, metastasis, drug resistance, and tumor invasion by stabilizing hypoxia-inducible factor-1 (HIF-1) (Wilson and Hay, 2011). HIF-1 is a heterodimeric transcription factor composed of α and β subunits (Wang and Semenza, 1995). Although HIF-1β is expressed constitutively, HIF-1α expression is tightly controlled by oxygen levels. HIF-1α is a central molecule involved in mediating the effects of hypoxia. Under hypoxic conditions, PHD activity is inhibited; thus, HIF-α can translocate to the nucleus, dimerize with HIF-1β, and activate the transcription of PD-L1 by binding to the hypoxia-response elements (HREs). (Li et al., 2015; Noman et al., 2014).

The detailed molecular mechanism of curcumol-mediated anti-tumor immunity is not well understood. In this study, we found that curcumol reduced the expression of phosphorylated (p)-STAT3 (T705) via JAK1, JAK2, and Src pathways and inhibited HIF-1α protein synthesis via mTOR/p70S6K/eIF4E and MAPK pathways. Furthermore, we revealed that crosstalk between STAT3 and HIF-1α pathways collaboratively regulated PD-L1 activation, and curcumol plays a role in this regulation. Moreover, curcumol inhibited the migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs) through the suppression of PD-L1. We also found that curcumol restored the tumor-killing activity of T-cells by inhibiting of PD-L1. The anti-tumor activity of curcumol was further confirmed in a murine xenograft model, and no apparent toxicity was observed in the animals. Curcumol may represent a promising lead compound for the development of new targeted anti-cancer therapeutics.

Section snippets

Cell culture and reagents

HeLa cervical cancer cells, A549 lung cancer cell, Hep3B human hepatocellular carcinoma cells and HUVEC cells were cultured in DMEM with penicillin (100 units/mL)-streptomycin (100 units/ml) (Invitrogen, Carlsbad, CA, USA) that was supplemented with 10% fetal bovine serum (Hyclone, Logan, UT, USA). These cells were purchased from FuHeng Cell Center (Shanghai, China). The hypoxic culture was kept in a gas-controlled chamber (Thermo Electron Corp. Marietta, OH, USA) maintained at 1% O₂, 94% N₂,

Curcumol suppresses constitutive STAT3 activation by JAK1, JAK2, and Src

It has been reported that the STAT3 pathway mediates the critical properties of tumor formation and progression, such as proliferation, metastasis, angiogenesis, and cell survival. Therefore, in this study, we examined whether curcumol affects STAT3 signaling. Fig. 1B, presents the possible curcumol binding at Tyr705 in p-STAT3. Subsequently, we performed STAT3 reporter assays to investigate whether curcumol modulated STAT3 transcriptional activation. STAT3 reporter gene expression was

Discussion

Curcumol has been demonstrated to directly exert anti-cancer effects on hepatic cancer cells by downregulating IDH1 (Zang et al., 2017). Additionally, recent studies described the molecular mechanism of the effects of curcumol on the induction of cell growth arrest and apoptosis in Jurkat cells, a model of CD4⁺ T-cells (Wang et al., 2014), suggesting that the anti-tumor effects of curcumol may also be linked to the immune response. In this study, our results supported this possibility by

Author contributions

Xuejun Jin and Juan Ma conceived and designed the study. Hong Xiang Zuo and Yong Jin performed all the experiments and wrote the manuscript. Zhe Wang, Zhi Hong Zhang, Ming Yue Li performed part of culture cell experiments. Jing Ying Wang, Yue Xing and Myong Hak Ri performed part of animal experiments. Guang Hua Xu provided the compound. Cheng Hua Jin, Lian Xun Piao, Juan Ma and Xuejun Jin reviewed and edited the manuscript. All authors read and approved the manuscript.

Declaration of competing interest

The authors declare that there are no financial conflicts of interest in regard to this work.

Acknowledgments

This work was partially supported by National Natural Science Foundation of China, No. 81660608 and 81760657. This work was partially supported by Jilin Province Science and Technology Development Outstanding Young Talents (20180520057JH) and the 13th five-year program of science and technology of the Ministry of Education of Jilin Province (JJKH20191152KJ).

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¹: These two authors equally contributed to this work.

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Curcumol inhibits the expression of programmed cell death-ligand 1 through crosstalk between hypoxia-inducible factor-1α and STAT3 (T705) signaling pathways in hepatic cancer

Highlights

Abstract

Ethnopharmacological relevance

Aim of the study

Materials and methods

Results

Conclusions

Graphical abstract

Introduction

Section snippets

Cell culture and reagents

Curcumol suppresses constitutive STAT3 activation by JAK1, JAK2, and Src

Discussion

Author contributions

Declaration of competing interest

Acknowledgments

J. Biol. Chem.

Cell

Redox Biol

Canc. Lett.

Chem. Biol. Interact.

J. Pharmaceut. Biomed. Anal.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Mol. Cell.

J. Biol. Chem.

J. Biol. Chem.

Int. Immunopharm.

Pharmacol. Res.

Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship?

Ann. N. Y. Acad. Sci.

Functional expression and impact of testis-specific gene antigen 10 in breast cancer: a combined in vitro and in silico analysis

Bioimpacts

The role of STATs in transcriptional control and their impact on cellular function

Oncogene

Antifungal activity, main active components and mechanism of Curcuma longa extract against Fusarium graminearum

PloS One

Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity

Nat. Rev. Immunol.

PKM2, STAT3 and HIF-1alpha: the Warburg's vicious circle

JAK-STAT

HIF-1alpha is overexpressed in leukemic cells from TP53-disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia

Haematologica