Research Paper Volume 15, Issue 22 pp 12873—12889
Silencing of Dicer enhances dacarbazine resistance in melanoma cells by inhibiting ADSL expression
- 1 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan
- 2 Division of Dermatology, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei 105, Taiwan
- 3 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- 4 Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei 235, Taiwan
- 5 Department of General Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- 6 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan
- 7 Department of Surgery, Division of Plastic and Reconstructive Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
- 8 Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 110, Taiwan
- 9 Department of Ophthalmology, Taipei City Hospital, Renai Branch, Taipei 106, Taiwan
- 10 Department of Ophthalmology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- 11 Department of Surgery, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 813, Taiwan
Received: June 13, 2023 Accepted: October 15, 2023 Published: November 15, 2023
https://doi.org/10.18632/aging.205207How to Cite
Copyright: © 2023 Yeh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Dacarbazine (DTIC) is the primary first-line treatment for advanced-stage metastatic melanoma; thus, DTIC resistance is poses a major challenge. Therefore, investigating the mechanism underlying DTIC resistance must be investigated. Dicer, a type III cytoplasmic endoribonuclease, plays a pivotal role in the maturation of miRNAs. Aberrant Dicer expression may contribute to tumor progression, clinical aggressiveness, and poor prognosis in various tumors. Dicer inhibition led to a reduction in DTIC sensitivity and an augmentation in stemness in melanoma cells. Clinical analyses indicated a low Dicer expression level as a predictor of poor prognosis factor. Metabolic alterations in tumor cells may interfere with drug response. Adenylosuccinate lyase (ADSL) is a crucial enzyme in the purine metabolism pathway. An imbalance in ADSL may interfere with the therapeutic efficacy of drugs. We discovered that DTIC treatment enhanced ADSL expression and that Dicer silencing significantly reduced ADSL expression in melanoma cells. Furthermore, ADSL overexpression reversed Dicer silencing induced DTIC resistance and cancer stemness. These findings indicate that Dicer-mediated ADSL regulation influences DTIC sensitivity and stemness in melanoma cells.
Abbreviations
ADSL: adenylosuccinate lyase; AICAR: aminoimidazole carboxamide ribotide; AMP: adenosine monophosphate; CT: chemotherapy; DTIC: dacarbazine; HCC: hepatocellular carcinoma; G6PDH: glucose-6-phosphate dehydrogenase; IHC: immunohistochemistry; MRP2: multidrug resistance protein 2; RT: radiation therapy; SAICAR: succinylaminoimidazole carboxamide ribotide; s-AMP: adenylosuccinate; SGLT1: sodium/glucose cotransporter 1; shADSL: short-hairpin RNA targeting ADSL; shDicer: short-hairpin RNA targeting Dicer; TCGA: The Cancer Genome Atlas; TNBC: triple-negative breast cancer.