Current issue
Archive
Manuscripts accepted
About the Journal
Editorial office
Editorial board
Section Editors
Abstracting and indexing
Subscription
Contact
Ethical standards and procedures
Most read articles
Instructions for authors
Article Processing Charge (APC)
Regulations of paying article processing charge (APC)
EXPERIMENTAL RESEARCH
Acetylshikonin (AceS) inhibited drug-resistant melanoma via downregulating matrix metalloproteinase-3 (MMP3)
1
Xiangyang Hospital of Traditional Chinese Medicine (Xiangyang Institute of Traditional Chinese Medicine), China
These authors had equal contribution to this work
Submission date: 2025-05-28
Final revision date: 2025-07-21
Acceptance date: 2025-08-16
Online publication date: 2025-10-17
Corresponding author
Guiyuan Deng
Xiangyang Hospital of Traditional Chinese Medicine (Xiangyang Institute of Traditional Chinese Medicine China
Xiangyang Hospital of Traditional Chinese Medicine (Xiangyang Institute of Traditional Chinese Medicine China
KEYWORDS
TOPICS
ABSTRACT
Introduction:
Drug resistance has become a huge challenge in melanoma. This study aimed to explore the molecular mechanism by which acetylshikonin (AceS) inhibits melanoma with drug resistance to BRAF inhibitor (BRAFi).
Material and methods:
To identify potential targets of AceS in drug-resistant melanoma, we intersected AceS targets predicted by SwissTargetPrediction and differentially expressed genes in drug-resistant melanoma identified from the GSE203545 dataset. Drug-resistant M14 cells were treated with AceS with or without PLX4720, a BRAFi. Cell proliferation, migration, invasion, and apoptosis were investigated. MMP3 was quantified by qPCR and immunofluorescence. Extracellular matrix (ECM) was evaluated by MMP1 and MMP9. Also, drug-resistant M14 cells were transfected by MMP3 siRNA. Moreover, drug-resistant M14 cells with MMP3 overexpression were treated with AceS. In vivo, a subcutaneous tumor-bearing nude mouse model was established to validate the effects of AceS in drug-resistant melanoma.
Results:
MMP3 was found to be the key target of AceS in drug-resistant melanoma. AceS significantly inhibited proliferation, migration, and invasion (p < 0.05), and promoted apoptosis (p < 0.05); it could increase the sensitivity of drug-resistant M14 cells to PLX4720 (p < 0.05). MMP3 silencing contributed to the decreases in proliferation, migration, and invasion, and the increased apoptosis (p < 0.05). Significantly, MMP3 overexpression reversed the effects caused by AceS (p < 0.05). AceS inhibited tumor growth; it reduced MMP1, MMP3, and MMP9 in vivo. AceS promoted tumor sensitivity to PLX4720 in vivo.
Conclusions:
AceS downregulated MMP3 to modulate ECM remodeling, thereby inhibiting drug-resistant melanoma, and enhanced the cell response to BRAFi. Our findings provide intriguing insights into drug-resistant melanoma.
Drug resistance has become a huge challenge in melanoma. This study aimed to explore the molecular mechanism by which acetylshikonin (AceS) inhibits melanoma with drug resistance to BRAF inhibitor (BRAFi).
Material and methods:
To identify potential targets of AceS in drug-resistant melanoma, we intersected AceS targets predicted by SwissTargetPrediction and differentially expressed genes in drug-resistant melanoma identified from the GSE203545 dataset. Drug-resistant M14 cells were treated with AceS with or without PLX4720, a BRAFi. Cell proliferation, migration, invasion, and apoptosis were investigated. MMP3 was quantified by qPCR and immunofluorescence. Extracellular matrix (ECM) was evaluated by MMP1 and MMP9. Also, drug-resistant M14 cells were transfected by MMP3 siRNA. Moreover, drug-resistant M14 cells with MMP3 overexpression were treated with AceS. In vivo, a subcutaneous tumor-bearing nude mouse model was established to validate the effects of AceS in drug-resistant melanoma.
Results:
MMP3 was found to be the key target of AceS in drug-resistant melanoma. AceS significantly inhibited proliferation, migration, and invasion (p < 0.05), and promoted apoptosis (p < 0.05); it could increase the sensitivity of drug-resistant M14 cells to PLX4720 (p < 0.05). MMP3 silencing contributed to the decreases in proliferation, migration, and invasion, and the increased apoptosis (p < 0.05). Significantly, MMP3 overexpression reversed the effects caused by AceS (p < 0.05). AceS inhibited tumor growth; it reduced MMP1, MMP3, and MMP9 in vivo. AceS promoted tumor sensitivity to PLX4720 in vivo.
Conclusions:
AceS downregulated MMP3 to modulate ECM remodeling, thereby inhibiting drug-resistant melanoma, and enhanced the cell response to BRAFi. Our findings provide intriguing insights into drug-resistant melanoma.
REFERENCES (37)
1.
Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024; 74: 229-63.
2.
Long GV, Swetter SM, Menzies AM, Gershenwald JE, Scolyer RA. Cutaneous melanoma. Lancet 2023; 402: 485-502.
3.
Timar J, Ladanyi A. Molecular pathology of skin melanoma: epidemiology, differential diagnostics, prognosis and therapy prediction. Int J Mol Sci 2022; 23: 5384.
4.
Colombino M, Casula M, Paliogiannis P, et al. Heterogeneous pathogenesis of melanoma: BRAF mutations and beyond. Crit Rev Oncol Hematol 2024; 201: 104435.
5.
Zhong J, Yan W, Wang C, et al. BRAF inhibitor resistance in melanoma: mechanisms and alternative therapeutic strategies. Curr Treat Options Oncol 2022; 23: 1503-21.
6.
Chen W, Park JI. Tumor cell resistance to the inhibition of BRAF and MEK1/2. Int J Mol Sci 2023; 24: 14837.
7.
Suhaimi SA, Chan SC, Rosli R. Matrix metallopeptidase 3 polymorphisms: emerging genetic markers in human breast cancer metastasis. J Breast Cancer 2020; 23: 1-9.
8.
Shao L, Liu W, Zhang C, et al. The role and function of secretory protein matrix metalloproteinase-3 (MMP3) in cervical cancer. Iran J Public Health 2024; 53: 855-66.
9.
Seehawer M, Li Z, Nishida J, et al. Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3. Nat Cell Biol 2024; 26: 1165-75.
10.
Quinones-Diaz BI, Reyes-Gonzalez JM, Sanchez-Guzman V, et al. MicroRNA-18a-5p suppresses tumor growth via targeting matrix metalloproteinase-3 in cisplatin-resistant ovarian cancer. Front Oncol 2020; 10: 602670.
11.
Lawicki P, Malinowski P, Motyka J, et al. Plasma levels of metalloproteinase 3 (MMP-3) and metalloproteinase 7 (MMP-7) as new candidates for tumor biomarkers in diagnostic of breast cancer patients. J Clin Med 2023; 12: 2618.
12.
Nunomura J, Nakano R, Naruke A, et al. Interleukin-1beta triggers matrix metalloprotease-3 expression through p65/RelA activation in melanoma cells. PLoS One 2022; 17: e0278220.
13.
Zhou S, Lu J, Liu S, et al. Role of the tumor microenvironment in malignant melanoma organoids during the development and metastasis of tumors. Front Cell Dev Biol 2023; 11: 1166916.
14.
Kalli M, Poskus MD, Stylianopoulos T, Zervantonakis IK. Beyond matrix stiffness: targeting force-induced cancer drug resistance. Trends Cancer 2023; 9: 937-54.
15.
Marusak C, Thakur V, Li Y, et al. Targeting extracellular matrix remodeling restores BRAF inhibitor sensitivity in BRAFi-resistant melanoma. Clin Cancer Res 2020; 26: 6039-50.
16.
Pittayapruek P, Meephansan J, Prapapan O, Komine M, Ohtsuki M. Role of matrix metalloproteinases in photoaging and photocarcinogenesis. Int J Mol Sci 2016; 17: 868.
17.
Lin H, Ma X, Yang X, et al. Natural shikonin and acetyl-shikonin improve intestinal microbial and protein composition to alleviate colitis-associated colorectal cancer. Int Immunopharmacol 2022; 111: 109097.
18.
Zhang Z, Shen C, Zhou F, Zhang Y. Shikonin potentiates therapeutic efficacy of oxaliplatin through reactive oxygen species-mediated intrinsic apoptosis and endoplasmic reticulum stress in oxaliplatin-resistant colorectal cancer cells. Drug Dev Res 2023; 84: 542-55.
19.
Lin SS, Chang TM, Wei AI, et al. Acetylshikonin induces necroptosis via the RIPK1/RIPK3-dependent pathway in lung cancer. Aging 2023; 15: 14900-14.
20.
Cha HS, Lee HK, Park SH, Nam MJ. Acetylshikonin induces apoptosis of human osteosarcoma U2OS cells by triggering ROS-dependent multiple signal pathways. Toxicol In Vitro 2023; 86: 105521.
21.
Jiang S, Wang H, Guo Y, Liu Z, Song W. Acetylshikonin inhibits the migration and invasion of A375 cells by reversing EMT process via the PI3K/Akt/mTOR pathway. Biotechnol Biotechnol Equipment 2019; 33: 699-706.
22.
Rossi A, Roberto M, Panebianco M, et al. Drug resistance of BRAF-mutant melanoma: review of up-to-date mechanisms of action and promising targeted agents. Eur J Pharmacol 2019; 862: 172621.
23.
Zhang Z, Bai J, Zeng Y, et al. Pharmacology, toxicity and pharmacokinetics of acetylshikonin: a review. Pharm Biol 2020; 58: 950-8.
24.
Shon JC, Phuc NM, Kim WC, et al. Acetylshikonin is a novel non-selective cytochrome P450 inhibitor. Biopharm Drug Dispos 2017; 38: 553-6.
25.
Hao G, Zhai J, Jiang H, et al. Acetylshikonin induces apoptosis of human leukemia cell line K562 by inducing S phase cell cycle arrest, modulating ROS accumulation, depleting Bcr-Abl and blocking NF-kappaB signaling. Biomed Pharmacother 2020; 122: 109677.
26.
Wang J, Iannarelli R, Pucciarelli S, et al. Acetylshikonin isolated from Lithospermum erythrorhizon roots inhibits dihydrofolate reductase and hampers autochthonous mammary carcinogenesis in Delta16HER2 transgenic mice. Pharmacol Res 2020; 161: 105123.
27.
Olczak M, Orzechowska MJ, Bednarek AK, Lipinski M. The transcriptomic profiles of ESR1 and MMP3 stratify the risk of biochemical recurrence in primary prostate cancer beyond clinical features. Int J Mol Sci 2023; 24: 8399.
28.
Polz A, Morshed K, Drop B, Polz-Dacewicz M. Could MMP3 and MMP9 serve as biomarkers in EBV-related oropharyngeal cancer. Int J Mol Sci 2024; 25: 2561.
29.
Hu HF, Xu WW, Zhang WX, et al. Identification of miR-515-3p and its targets, vimentin and MMP3, as a key regulatory mechanism in esophageal cancer metastasis: functional and clinical significance. Signal Transduct Target Ther 2020; 5: 271.
30.
Liang M, Wang J, Wu C, et al. Targeting matrix metalloproteinase MMP3 greatly enhances oncolytic virus mediated tumor therapy. Transl Oncol 2021; 14: 101221.
31.
Taha EA, Sogawa C, Okusha Y, et al. Knockout of MMP3 weakens solid tumor organoids and cancer extracellular vesicles. Cancers 2020; 12: 1260.
32.
Yuan Z, Li Y, Zhang S, et al. Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments. Mol Cancer 2023; 22: 48.
33.
Prakash J, Shaked Y. The interplay between extracellular matrix remodeling and cancer therapeutics. Cancer Discov 2024; 14: 1375-88.
34.
Popovic A, Tartare-Deckert S. Role of extracellular matrix architecture and signaling in melanoma therapeutic resistance. Front Oncol 2022; 12: 924553.
35.
Vempati P, Karagiannis ED, Popel AS. A biochemical model of matrix metalloproteinase 9 activation and inhibition. J Biol Chem 2007; 282: 37585-96.
36.
Steenport M, Khan KM, Du B, et al. Matrix metalloproteinase (MMP)-1 and MMP-3 induce macrophage MMP-9: evidence for the role of TNF-alpha and cyclooxygenase-2. J Immunol 2009; 183: 8119-27.
37.
Alge-Priglinger CS, Kreutzer T, Obholzer K, et al. Oxidative stress-mediated induction of MMP-1 and MMP-3 in human RPE cells. Invest Ophthalmol Vis Sci 2009; 50: 5495-503.
Share
RELATED ARTICLE
| eISSN: | 1896-9151 |
| ISSN: | 1734-1922 |
We process personal data collected when visiting the website. The function of obtaining information about users and their behavior is carried out by voluntarily entered information in forms and saving cookies in end devices. Data, including cookies, are used to provide services, improve the user experience and to analyze the traffic in accordance with the Privacy policy. Data are also collected and processed by Google Analytics tool (more).
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
