Octyl Gallate Induces Pancreatic Ductal Adenocarcinoma Cell Apoptosis and Suppresses Endothelial-Mesenchymal Transition-Promoted M2-Macrophages, HSP90α Secretion, and Tumor Growth

Abstract

Octyl gallate (OG) is a common antioxidant and preservative safely used in food additive and cosmetics. In this study, OG exhibited an activity to induce apoptosis in pancreatic ductal adenocarcinoma (PDAC) cells. It induced BNIP3L level and facilitated physical associations of BNIP3L with Bcl-2 as well as Bcl-XL to set the mitochondrial Bax/Bak channels free for cytochrome c release. In addition, in vivo evaluation also showed that daily oral administration of OG was efficacious to prevent the tumor growth of PDAC cell grafts. Considering PDAC is a desmoplastic tumor consisting of many cancer-associated fibroblasts (CAFs), we further evaluated the efficacy of OG in a CAFs-involved PDAC mouse model. Endothelial-to-mesenchymal transition (EndoMT) is an important source of CAFs. The mix of EndoMT-derived CAFs with PDAC cell grafts significantly recruited myeloid-derived macrophages but prevented immune T cells. HSP90α secreted by EndoMT-derived CAFs further induced macrophage M2-polarization and more HSP90α secretion to expedite PDAC tumor growth. OG exhibited its potent efficacy against the tumor growth, M2-macrophages, and serum HSP90α level in the EndoMT-involved PDAC mouse model. CD91 and TLR4 are cell-surface receptors for extracellular HSP90α (eHSP90α). OG blocked eHSP90α–TLR4 ligation and, thus, prevented eHSP90α-induced M2-macrophages and more HSP90α secretion from macrophages and PDAC cells.

Modulation of TLR/NF-κB/NLRP Signaling by Bioactive Phytocompounds: A Promising Strategy to Augment Cancer Chemotherapy and Immunotherapy

“…The results demonstrated that combination of quercetin with chrysin suppressed the migration and invasion of nickel via downregulation of TLR4/NF-κB signaling in human lung cancer cells in vitro ( 134 ). Octyl gallate exerted significant efficacy against heat shock protein 90α (HSP90α) levels, eHSP90α–TLR4 ligation, M2-macrophages, and tumor growth in a pancreatic ductal adenocarcinoma mouse model ( 135 ).…”

Extracellular HSP90α Induces MyD88-IRAK Complex-Associated IKKα/β−NF-κB/IRF3 and JAK2/TYK2−STAT-3 Signaling in Macrophages for Tumor-Promoting M2-Polarization

“…These macrophages secrete not only significant amounts of HSP90α but also IL-6 and IL-8 to stimulate a Janus kinase 2 (JAK2)/tyrosine kinase 2 (TYK2)-signal transducer and activator of transcription-3 (STAT-3) signaling pathway in pancreatic ductal epithelial cells to express and secrete more HSP90α [ 23 ]. Moreover, eHSP90α per se also stimulates significant HSP90α expression and secretion from macrophages and epithelial cells [ 14 , 24 ]. In the resultant eHSP90α-rich tissue microenvironment, eHSP90α would not only be a potent inducer of HSP90α-secreting M2-type macrophages, but also acts as a promoter of EMT, migration, and invasion of pancreatic ductal epithelial cells [ 14 , 23 , 24 ].…”

“…Moreover, eHSP90α per se also stimulates significant HSP90α expression and secretion from macrophages and epithelial cells [ 14 , 24 ]. In the resultant eHSP90α-rich tissue microenvironment, eHSP90α would not only be a potent inducer of HSP90α-secreting M2-type macrophages, but also acts as a promoter of EMT, migration, and invasion of pancreatic ductal epithelial cells [ 14 , 23 , 24 ]. Besides functioning in malignant progression, TIMs and the associated eHSP90α are also critically involved in the development of PDAC.…”

Gallic acid enhances the antitumor activity of Icotinib hydrochloride in non-small cell lung cancer via of Hippo-YAP signaling pathway in vitro and in vivo

“…According to researches, GA may stop the development of malignant tumors by stopping the propagation and aggressive activity of tumors [7][8][9][10][11]. Also, GA exerts an excellent inhibitory effect on the tumors such as cervical cancer [12], breast cancer [11], lung cancer [13] and prostate cancer [14].…”