PMID- 37951196
OWN - NLM
STAT- MEDLINE
DCOM- 20231121
LR  - 20231129
IS  - 1878-1705 (Electronic)
IS  - 1567-5769 (Linking)
VI  - 125
IP  - Pt B
DP  - 2023 Dec
TI  - Eicosapentaenoic acid enhances the sensitivity of osteosarcoma to cisplatin by 
      inducing ferroptosis through the DNA-PKcs/AKT/NRF2 pathway and reducing PD-L1 
      expression to attenuate immune evasion.
PG  - 111181
LID - S1567-5769(23)01507-2 [pii]
LID - 10.1016/j.intimp.2023.111181 [doi]
AB  - Acquired drug resistance poses a significant challenge in osteosarcoma therapy. 
      Therefore, it is necessary for us to discover and develop an alternative 
      anti-cancer strategy. Previous studies have shown that eicosapentaenoic acid 
      (EPA) significantly increases chemosensitivity in cancer cells. In this study, we 
      discovered that EPA enhances the sensitivity of osteosarcoma to cisplatin (DDP). 
      Interestingly, in addition to inhibiting growth and inducing apoptosis, EPA also 
      enhances DDP-induced ferroptosis. Western blot analysis confirmed that EPA 
      treatment significantly decreases the expression of DNA-dependent protein kinase 
      catalytic subunit (DNA-PKcs), p-AKT, nuclear factor erythroid 2-related factor 2 
      (NRF2), and glutathione peroxidase 4 (GPX4) in cells. Knockdown of DNA-PKcs by 
      siRNA further enhances the level of ferroptosis induced by EPA. Importantly, EPA 
      can reverse the high expression level of programmed death ligand 1 (PD-L1) 
      induced by DDP. ELISA and western blotting analysis revealed that EPA treatment 
      decreases the levels of IL-6 and p-STAT3, which are increased by DDP treatment. 
      Furthermore, a co-immunoprecipitation (co-IP) assay confirmed the interaction 
      between DNA-PKcs and PD-L1, and knockdown of DNA-PKcs further reduces the 
      expression of PD-L1. This data provides the first evidence that EPA suppresses 
      the DNA-PKcs/AKT/NRF2/GPX4 pathway to enhance ferroptosis, and inhibits 
      IL-6/STAT3 and DNA-PKcs to decrease PD-L1 expression, thereby sensitizing 
      osteosarcoma to DDP. The combination of EPA and DDP presents an encouraging and 
      promising anti-tumor strategy.
CI  - Copyright (c) 2023. Published by Elsevier B.V.
FAU - Zhang, Yining
AU  - Zhang Y
AD  - The First Clinical College of Cheeloo College of Medicine, Shandong University, 
      250012 Jinan, Shandong, China; Department of Orthopaedics, Qilu Hospital of 
      Shandong University, 250012 Jinan, Shandong, China.
FAU - Shen, Guohong
AU  - Shen G
AD  - Department of Pediatrics, Central Hospital Affiliated to Shandong First Medical 
      University, Jinan, Shandong 250013, China.
FAU - Meng, Tingting
AU  - Meng T
AD  - Research Center of Translational Medicine, Central Hospital Affiliated to 
      Shandong First Medical University, Jinan, Shandong 250013, China.
FAU - Lv, Zhaorui
AU  - Lv Z
AD  - The First Clinical College of Cheeloo College of Medicine, Shandong University, 
      250012 Jinan, Shandong, China; Department of Orthopaedics, Qilu Hospital of 
      Shandong University, 250012 Jinan, Shandong, China.
FAU - Li, Xin
AU  - Li X
AD  - Department of Orthopaedics, Qilu Hospital of Shandong University, 250012 Jinan, 
      Shandong, China.
FAU - Li, Jianmin
AU  - Li J
AD  - Department of Orthopaedics, Qilu Hospital of Shandong University, 250012 Jinan, 
      Shandong, China.
FAU - Li, Ka
AU  - Li K
AD  - Department of Orthopaedics, Qilu Hospital of Shandong University, 250012 Jinan, 
      Shandong, China. Electronic address: osteolk@email.sdu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20231109
PL  - Netherlands
TA  - Int Immunopharmacol
JT  - International immunopharmacology
JID - 100965259
RN  - Q20Q21Q62J (Cisplatin)
RN  - 0 (CD274 protein, human)
RN  - 0 (B7-H1 Antigen)
RN  - AAN7QOV9EA (Eicosapentaenoic Acid)
RN  - 0 (NF-E2-Related Factor 2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (DNA-Activated Protein Kinase)
RN  - 0 (Interleukin-6)
RN  - 9007-49-2 (DNA)
SB  - IM
MH  - Humans
MH  - Cisplatin/pharmacology
MH  - B7-H1 Antigen
MH  - Eicosapentaenoic Acid/pharmacology
MH  - NF-E2-Related Factor 2
MH  - Proto-Oncogene Proteins c-akt
MH  - *Ferroptosis
MH  - Immune Evasion
MH  - DNA-Activated Protein Kinase
MH  - Interleukin-6
MH  - *Osteosarcoma/drug therapy
MH  - *Bone Neoplasms/drug therapy
MH  - DNA
OTO - NOTNLM
OT  - DDP
OT  - EPA
OT  - Ferroptosis
OT  - Osteosarcoma
OT  - PD-L1
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/11/12 00:41
MHDA- 2023/11/21 06:43
CRDT- 2023/11/11 18:15
PHST- 2023/09/06 00:00 [received]
PHST- 2023/10/29 00:00 [revised]
PHST- 2023/11/01 00:00 [accepted]
PHST- 2023/11/21 06:43 [medline]
PHST- 2023/11/12 00:41 [pubmed]
PHST- 2023/11/11 18:15 [entrez]
AID - S1567-5769(23)01507-2 [pii]
AID - 10.1016/j.intimp.2023.111181 [doi]
PST - ppublish
SO  - Int Immunopharmacol. 2023 Dec;125(Pt B):111181. doi: 
      10.1016/j.intimp.2023.111181. Epub 2023 Nov 9.