Shikonin-mediated PD-L1 degradation suppresses immune evasion in pancreatic cancer by inhibiting NF-κB/STAT3 and NF-κB/CSN5 signaling pathways

Ruan, Zhiyan; Liang, Minhua; Shang, Ling; Lai, Manxiang; Deng, Xiangliang; Su, Xiaolu

doi:10.1016/j.pan.2021.01.023

Cited by 34 publications

(23 citation statements)

References 52 publications

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“…With this background, western blot analyses were performed to determine whether shikonin-induced apoptosis in chondrosarcoma cells is mediated by MAPK signaling pathways. The inhibitory effect of STAT3 phosphorylation by shikonin has already been shown in various tumor types, such as pancreatic cancer [ 36 ], melanoma [ 37 ], or lung cancer [ 38 ]. We were able to demonstrate, especially in Cal78 chondrosarcoma cells, a significant reduction of STAT3 phosphorylation after treatment with all shikonin derivatives.…”

Section: Discussionmentioning

confidence: 99%

Shikonin derivatives cause apoptosis and cell cycle arrest in human chondrosarcoma cells via death receptors and MAPK regulation

et al. 2022

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Background Although chondrosarcoma is the second most common primary malignant bone tumor, treatment options are limited due to its extensive resistance to a chemo- and radiation therapy. Since shikonin has shown potent anticancer activity in various types of cancer cells, it represents a promising compound for the development of a new therapeutic approach. Methods The dose-relationships of shikonin and its derivatives acetylshikonin and cyclopropylshikonin on two human chondrosarcoma cell lines were measured using the CellTiter-Glo®. The changes in the cell cycle were presented by flow cytometry. Protein phosphorylation and expression apoptotic markers, MAPKs and their downstream targets were analyzed using western blotting and gene expression were evaluated using RT-qPCR. Results Chondrosarcoma cells showed a dose-dependent inhibition of cell viability after treatment with shikonin and its derivatives, with the strongest effect for shikonin and IC50 values of 1.3 ± 0.2 µM. Flow cytometric measurements revealed a G2/M arrest of the cells after treatment. Protein and gene expression analysis demonstrated a dose-dependent downregulation of survivin and XIAP, and an upregulation of Noxa, γH2AX, cleaved caspase-8, -9, -3, and -PARP. Furthermore, the expression of various death receptors was modulated. As MAPK signaling pathways play a key role in tumor biology, their phosphorylation pattern and their corresponding downstream gene regulation were analyzed. Treatment with shikonin derivatives caused an inhibition of pSTAT3 and an increase of pAKT and the MAPKs pERK, pJNK, and pp38 in a dose-dependent manner. Conclusions These data demonstrated the significant anti-tumorigenic effect of shikonin derivatives in chondrosarcoma and encourage further research.

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Section: Discussionmentioning

confidence: 99%

Shikonin derivatives cause apoptosis and cell cycle arrest in human chondrosarcoma cells via death receptors and MAPK regulation

et al. 2022

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“…Shikonin is a naturally occurring naphthoquinone isolated from the root of the plant Lithospermum erythrorhizon, which has been widely used in the treatment of various disease [8]. In the recent years, studies have shown that shikonin and its derivatives have antitumor effects in wide range of cancer types including breast [9], lung [10], ovarian [11], liver [12], prostate [13], gastric [14] and pancreatic cancer [15]. However, the effects of shikonin in colorectal cancer cells have not been yet fully investigated yet.…”

Section: Introductionmentioning

confidence: 99%

Shikonin induced Apoptosis Mediated by Endoplasmic Reticulum Stress in Colorectal Cancer Cells

Qi¹,

Zhang²,

Liu³

et al. 2022

J. Cancer

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Shikonin is a naphthoquinone pigment isolated from the root of Lithospermum erythrorhizon, which has displayed potent anti-tumor properties. However, the effects of shikonin in colorectal cancer cells have not been yet fully investigated. In this study, we demonstrated that shikonin significantly inhibited the activity of colorectal cancer cells in a time-and dose-dependent manner. The flow cytometry and western blot results indicated that shikonin induced cell apoptosis by down-regulating BCL-2 and activating caspase-3/9 and the cleavage of PARP. The expression of BiP and the PERK/elF2α/ATF4/CHOP and IRE1α /JNK signaling pathways were upregulated after shikonin treatment. The pre-treatment with N-acetyl cysteine significantly reduced the cytotoxicity of shikonin. Taken together, shikonin could inhibit proliferation of the colorectal cancer cell through the activation of ROS mediated-ER stress. The in vivo results showed that shikonin effectively inhibited tumor growth in the HCT-116 and HCT-15 xenograft models. In conclusion, shikonin inhibited the proliferation of colorectal cancer cells in vitro and in vivo and warrants future investigation.

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“…Cyclin D1 is a cell cycle regulator and promotes progression through the G 1 -S phase. In human lung cancer and pancreatic cells, shikonin suppressed cell proliferation through modulating the expression of the cell cycle regulators such as cyclin D1 or cMyc [ 36 , 37 ].…”

Section: Resultsmentioning

confidence: 99%

Shikonin Derivatives Inhibit Inflammation Processes and Modulate MAPK Signaling in Human Healthy and Osteoarthritis Chondrocytes

Lohberger

Kaltenegger

Eck

et al. 2022

IJMS

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Osteoarthritis (OA) is the most common joint disorder and is characterized by the degeneration of articular cartilage. To develop new therapeutic approaches, we investigated the effect of shikonin derivatives on inflammation, MMP expression, and the regulation of MAPK signaling in human healthy (HC) and OA chondrocytes (pCH-OA). Viability was analyzed using the CellTiter-Glo® Assay. Inflammatory processes were investigated using a proteome profiler™ assay. Furthermore, we analyzed the effects of the shikonin derivatives by protein expression analysis of the phosphorylation pattern and the corresponding downstream gene regulation using RT-qPCR. Both HC and pCH-OA showed a dose-dependent decrease in viability after treatment. The strongest effects were found for shikonin with IC50 values of 1.2 ± 0.1 µM. Shikonin counteracts the inflammatory response by massively reducing the expression of the pro-inflammatory mediators. The phosphorylation level of ERK changed slightly. pJNK and pp38 showed a significant increase, and the downstream targets c/EBPs and MEF2c may play a role in the cartilage homeostasis. STAT3 phosphorylation decreased significantly and has a chondroprotective function through the regulation of cyclin D1 and Sox9. Our results demonstrate for the first time that shikonin derivatives have extensive effects on the inflammatory processes, MAPKs, and IL6/STAT3 downstream regulation in healthy and OA chondrocytes.

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Shikonin-mediated PD-L1 degradation suppresses immune evasion in pancreatic cancer by inhibiting NF-κB/STAT3 and NF-κB/CSN5 signaling pathways

Cited by 34 publications

References 52 publications

Shikonin derivatives cause apoptosis and cell cycle arrest in human chondrosarcoma cells via death receptors and MAPK regulation

Shikonin derivatives cause apoptosis and cell cycle arrest in human chondrosarcoma cells via death receptors and MAPK regulation

Shikonin induced Apoptosis Mediated by Endoplasmic Reticulum Stress in Colorectal Cancer Cells

Shikonin Derivatives Inhibit Inflammation Processes and Modulate MAPK Signaling in Human Healthy and Osteoarthritis Chondrocytes

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