Gao Zachary, Janakiraman Harinarayanan, Xiao Yang, Kang Sung Wook, Dong Jiangling, Choi Jasmine, Ogretmen Besim, Lee Hyun-Sung, Camp Ernest Ramsay
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
Dan L. Duncan Comprehensive Cancer Center, Houston, TX 77030, USA.
World J Oncol. 2024 Apr;15(2):169-180. doi: 10.14740/wjon1768. Epub 2024 Mar 21.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer resistant to current therapies, including oxaliplatin (Oxa). Growing evidence supports the ability of cancers to harness sphingolipid metabolism for survival. Sphingosine-1-phosphate (S1P) is an anti-apoptotic, pro-survival mediator that can influence cellular functions such as endoplasmic reticulum (ER) stress. We hypothesize that PDAC drives dysregulated sphingolipid metabolism and that S1P inhibition can enhance ER stress to improve therapeutic response to Oxa in PDAC.
RNA sequencing data of sphingolipid mediators from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Project (GTEx) datasets were analyzed. Murine and human PDAC cell lines were treated with small interfering RNA (siRNA) against sphingosine kinase-2 (SPHK2) or ABC294640 (ABC) and incubated with combinations of vehicle control or Oxa. In an orthotopic syngeneic KPC PDAC model, tumors were treated with either vehicle control, Oxa, ABC, or combination therapy.
RNA sequencing analysis revealed multiple significantly differentially expressed sphingolipid mediators (P < 0.05). , both siRNA knockdown of SPHK2 and ABC sensitized cells to Oxa therapy (P < 0.05), and induced eukaryotic initiation factor 2α (eIF2α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) phosphorylation, hallmarks of ER stress. therapy also increased extracellular high mobility group box 1 (HMGB1) release (P < 0.05), necessary for immunogenic cell death (ICD). combination therapy increased apoptotic markers as well as the intensity of HMGB1 staining compared to control (P < 0.05).
Our evidence suggests that sphingolipid metabolism is dysregulated in PDAC. Furthermore, S1P inhibition can sensitize PDAC to Oxa therapy through increasing ER stress and can potentiate ICD induction. This highlights a potential therapeutic target for chemosensitizing PDAC as well as an adjunct for future chemoimmunotherapy strategies.
胰腺导管腺癌（PDAC）是一种侵袭性癌症，对包括奥沙利铂（Oxa）在内的当前疗法具有抗性。越来越多的证据支持癌症利用鞘脂代谢来生存的能力。鞘氨醇-1-磷酸（S1P）是一种抗凋亡、促生存介质，可影响内质网（ER）应激等细胞功能。我们假设PDAC驱动鞘脂代谢失调，并且S1P抑制可增强ER应激，以改善PDAC对Oxa的治疗反应。
分析了来自癌症基因组图谱（TCGA）和基因型-组织表达项目（GTEx）数据集的鞘脂介质的RNA测序数据。用针对鞘氨醇激酶-2（SPHK2）或ABC294640（ABC）的小干扰RNA（siRNA）处理小鼠和人PDAC细胞系，并与溶媒对照或Oxa组合孵育。在原位同基因KPC PDAC模型中，用溶媒对照、Oxa、ABC或联合疗法治疗肿瘤。
RNA测序分析揭示了多种显著差异表达的鞘脂介质（P<0.05）。SPHK2和ABC的siRNA敲低均使细胞对Oxa治疗敏感（P<0.05），并诱导真核起始因子2α（eIF2α）和蛋白激酶RNA样内质网激酶（PERK）磷酸化，这是ER应激的标志。ABC疗法还增加了细胞外高迁移率族蛋白B1（HMGB1）的释放（P<0.05），这是免疫原性细胞死亡（ICD）所必需的。与对照相比，联合疗法增加了凋亡标志物以及HMGB1染色的强度（P<0.05）。
我们的证据表明PDAC中鞘脂代谢失调。此外，S1P抑制可通过增加ER应激使PDAC对Oxa治疗敏感，并可增强ICD诱导。这突出了一个使PDAC化疗增敏的潜在治疗靶点以及未来化学免疫治疗策略的辅助手段。
