Abstract
Simple SummaryPancreatic ductal adenocarcinoma (PDAC), comprising 90–95% of all pancreatic cancers, is one of the deadliest human cancers, with a gloomy prognosis and ~6-month median survival in metastatic tumors. Even patients with resectable tumors show a poor survival rate after surgery. Thus, PDAC represents an unmet therapeutic challenge. The aim of this review was to put into context the conundrum of pancreatic cancer treatment and the advent of a novel therapeutic approach, examining: (a) anatomical factors, demographics, statistics, and therapeutic approaches, affecting tumor detection, treatment, and prognosis; (b) the importance of the endoplasmic reticulum as a major target for pancreatic cancer due to its high abundance and activity in pancreatic cells; (c) the identification of the alkylphospholipid analog edelfosine as a novel drug against pancreatic cancer, showing two outstanding features—selective uptake by tumor tissue, and direct accumulation in the endoplasmic reticulum, leading to persistent endoplasmic reticulum stress and subsequent apoptosis.Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy—the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells—including pancreatic cancer cells—and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.
Highlights
As a novel mechanism favoring Jun NH2-terminal kinase (JNK) activation, we found a new chaperoning role of heat shock protein 90 (Hsp90) on JNK-mediated apoptosis, following the recruitment of Hsp90 and JNK in lipid rafts, as assessed by lipid raft isolation followed by co-immunoprecipiation as well as by immunoelectron microscopy in hematological cancer cells [221]
We suggest that the induction of sustained Endoplasmic reticulum (ER)-stress-mediated apoptosis by edelfosine could be further potentiated by its combined use with additional ER stress inducers
Based on RNA silencing experiments and biochemical approaches, we have recently found that the release of neutrophil-derived arginase-1 leads to arginine depletion which, in turn, induces ER stress in pancreatic cancer cells through the activation of the PERK→eiF2α→ATF4→CCAAT/enhancer-binding protein homologous protein (CHOP) axis, and eventually leads to cell death [239]
Summary
65–75% of all pancreatic cancers occur within the head and neck of the pancreas, whereas ~15–25% occur in the body and tail; the remaining lesions diffusely involve the whole gland. People with tumors in the body or tail of the pancreas have lower survival rates than those with cancer in the head or neck of the pancreas, independently of the presentation stage and extent of the disease [2,3]. The exocrine pancreas comprises acinar, ductal, and centroacinar cells [6], which form the exocrine glands and ducts, producing enzymes that are secreted into the duodenum (Figure 1a,b). Ductal cells form an intricate network of small tubes (ducts), by which the acinar-cell-secreted enzymes (e.g., proteases, amylases, lipases) flow into the main pancreatic duct The latter joins the common bile duct (carrying bile from the liver and the gallbladder through the pancreas) to form the ampulla of Vater, through which the bile and pancreatic juices enter the duodenum to break down proteins, carbohydrates, and fats (Figure 1a,b). Pancreatic cancer is projected to become the third leading cause of cancer-related death in the European Union—after lung and colorectal cancers—by 2025 [31], and the second leading cause of cancer death in the United States by 2030 [32]
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