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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer, which is usually diagnosed late and is nearly resistant to all conventional chemotherapy and radiotherapy
Accumulating evidence has shown that stromal components such as cancer-associated fibroblasts (CAFs), myeloid-derived macrophages, and extracellular matrix can interact with cancer cells to facilitate pancreatic ductal adenocarcinoma (PDAC) development and malignant progression [1]
Mitochondrial cytochrome c was decreased in the PDAC cells treated with Octyl gallate (OG) (Figure 2A)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer, which is usually diagnosed late and is nearly resistant to all conventional chemotherapy and radiotherapy. One of the crucial factors contributing to the aggressiveness of PDAC is the distinct and flourishing desmoplastic reaction in the tumor microenvironment [1]. Accumulating evidence has shown that stromal components such as cancer-associated fibroblasts (CAFs), myeloid-derived macrophages, and extracellular matrix can interact with cancer cells to facilitate PDAC development and malignant progression [1]. More understanding of the desmoplastic microenvironment of PDAC will be the bases for further studies on how to prevent disease progression and improve therapeutic efficacy. With regard to CAFs, they constitute the majority of tumor stromal cells and arise from diverse resources, such as tissue-resident fibroblasts, mesenchymal stem/progenitor cells, stellate cells, and infiltrating fibrocytes [2]. The endothelial-to-mesenchymal transition (EndoMT) of endothelial cells is an important resource contributing to 30–40% of CAFs [3]. EndoMT-derived CAFs can exhibit a potent tumor-promoting effect by secreting proteins like HSP90α, TGF-β, and soluble
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