Chemotherapy and autophagy-mediated cell death in pancreatic cancer cells (original) (raw)
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Autophagy is activated in pancreatic cancer cells and correlates with poor patient outcome
Cancer Science, 2008
Because autonomous proliferating cancer cells are often exposed to hypoxic conditions, there must be an alternative metabolic pathway, such as autophagy, that allows them to obtain energy when both oxygen and glucose are depleted. We previously reported finding that autophagy actually contributes to cancer cell survival in colorectal cancers both in vitro and in vivo. Pancreatic cancer remains a devastating and poorly understood malignancy, and hypoxia in pancreatic cancers is known to increase their malignant potential. In the present study archival pancreatic cancer tissue was retrieved from 71 cases treated by curative pancreaticoduodenectomy. Autophagy was evaluated by immunohistochemical staining with anti-LC3 antibody, as LC3 is a key component of autophagy and has been used as a marker of autophagy. The results showed that strong LC3 expression in the peripheral area of pancreatic cancer tissue was correlated with a poor outcome (P = 0.0170) and short disease-free period (P = 0.0118). Two of the most significant correlations among the clinicopathological factors tested were found between the peripheral intensity level of LC3 expression and tumor size (P = 0.0098) or tumor necrosis (P = 0.0127). Activated autophagy is associated with pancreatic cancer cells, and autophagy is thought to be a response to factors in the cancer microenvironment, such as hypoxia and poor nutrient supply. This is the first study to report the clinicopathological significance of autophagy in pancreatic cancer. (Cancer Sci 2008; 99: 1813-1819) C ancers are abnormal tissue masses whose growth exceeds and is uncoordinated with that of adjacent normal tissues, and which persist in the same excessive manner after cessation of the stimulus that evoked them. (1) All cancers ultimately depend on the host for their nutrition and blood supply, but as the preexisting vasculature is obviously insufficient to support the cancers' unlimited requirements for energy and nutrition as a result of their unregulated growth, angiogenesis has been considered pivotal to providing proliferating cancer cells with an adequate source of oxygen, energy, and nutrients. However, recent studies have revealed that even after new blood vessels have formed, both the oxygen and glucose supply is insufficient for the aggressively proliferating cancer cells in locally advanced cancers. Tumor hypoxia has been used as a marker of poor prognosis; (5,6) however, how cancer cells become more malignant or survive with an extremely poor blood supply, as for example in pancreatic cancer, is poorly understood. (7) When cancer cells are exposed to hypoxia, anaerobic glycolysis increases and provides energy for cell survival, but as the glucose supply is also insufficient because of the poor blood supply, there must be an alternative metabolic pathway that provides energy when both oxygen and glucose are depleted. We have reported that several cancer cell lines, including pancreatic cancer-and colorectal cancer-derived cell lines, are resistant to nutrient-deprived conditions. We have named this starvation-resistant phenotype 'austerity' and speculated that austerity may contribute to cancer cell survival in a nutrient-deficient microenvironment. Autophagy has long been known to be a non-specific selfdegradation mechanism that is triggered by nutrient deprivation, but recently it has been shown to play an important role in removing redundant or faulty cell components, such as damaged mitochondria and other organelles that are targeted for lysosomal degradation. The autophagic process occurs in three steps: (1) autophagosome formation; (2) lysosomal fusion with the autophagosome; and (3) lysosomal degradation. In step 1, a cup-shaped lipid bilayer called the isolation membrane is formed and engulfs cytosolic components, including organelles. In step 2, the isolation membrane closes, forming an autophagosome. Cytosolic LC3 (microtubuleassociated protein 1 light chain 3), a mammalian homolog of yeast ATG8, is converted to LC3-I (soluble unlipidated form of LC3) during this step and LC3-I is then modified to form LC-3-II (a membrane-bound form) and becomes localized on autophagosomes. Autophagosomes fuse with lysosomes to form autolysosomes. In step 3, the contents of the autolysosomes are degraded rapidly by lysosomal hydrolases, including cathepsins B, D, and L. Intra-autophagosomal LC3-II is also degraded at the same time. Thus, LC3 is a key component of autophagy, and it has been used as a marker of autophagy.
Therapeutic Aspects and Molecular Targets of Autophagy to Control Pancreatic Cancer Management
Biomedicines
Pancreatic cancer (PC) begins within the organ of the pancreas, which produces digestive enzymes, and is one of the formidable cancers for which appropriate treatment strategies are urgently needed. Autophagy occurs in the many chambers of PC tissue, including cancer cells, cancer-related fibroblasts, and immune cells, and can be fine-tuned by various promotive and suppressive signals. Consequently, the impacts of autophagy on pancreatic carcinogenesis and progression depend greatly on its stage and conditions. Autophagy inhibits the progress of preneoplastic damage during the initial phase. However, autophagy encourages tumor formation during the development phase. Several studies have reported that both a tumor-promoting and a tumor-suppressing function of autophagy in cancer that is likely cell-type dependent. However, autophagy is dispensable for pancreatic ductal adenocarcinoma (PDAC) growth, and clinical trials with autophagy inhibitors, either alone or in combination with oth...
The Role of Autophagy in Pancreatic Cancer: From Bench to the Dark Bedside
Cells, 2020
Pancreatic cancer is one of the deadliest cancer types urgently requiring effective therapeutic strategies. Autophagy occurs in several compartments of pancreatic cancer tissue including cancer cells, cancer associated fibroblasts, and immune cells where it can be subjected to a multitude of stimulatory and inhibitory signals fine-tuning its activity. Therefore, the effects of autophagy on pancreatic carcinogenesis and progression differ in a stage and context dependent manner. In the initiation stage autophagy hinders development of preneoplastic lesions; in the progression stage however, autophagy promotes tumor growth. This double-edged action of autophagy makes it a hard therapeutic target. Indeed, autophagy inhibitors have not yet shown survival improvements in clinical trials, indicating a need for better evaluation of existing results and smarter targeting techniques. Clearly, the role of autophagy in pancreatic cancer is complex and many aspects have to be considered when mo...
Pancreatic cancers require autophagy for tumor growth
Genes & Development, 2011
Macroautophagy (autophagy) is a regulated catabolic pathway to degrade cellular organelles and macromolecules. The role of autophagy in cancer is complex and may differ depending on tumor type or context. Here we show that pancreatic cancers have a distinct dependence on autophagy. Pancreatic cancer primary tumors and cell lines show elevated autophagy under basal conditions. Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. Together, these ultimately result in significant growth suppression of pancreatic cancer cells in vitro. Most importantly, inhibition of autophagy by genetic means or chloroquine treatment leads to robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models. These results suggest that, unlike in other cancers where autophagy inhibition may synergize with chemotherapy or targeted agents by preventing the up-regulation of autophagy as a reactive survival mechanism, autophagy is actually required for tumorigenic growth of pancreatic cancers de novo, and drugs that inactivate this process may have a unique clinical utility in treating pancreatic cancers and other malignancies with a similar dependence on autophagy. As chloroquine and its derivatives are potent inhibitors of autophagy and have been used safely in human patients for decades for a variety of purposes, these results are immediately translatable to the treatment of pancreatic cancer patients, and provide a much needed, novel vantage point of attack.
Interplay between autophagy and apoptosis in pancreatic tumors in response to gemcitabine
Targeted Oncology, 2013
Pancreatic cancer is an aggressive disease. Its incidence has increased over the last two decades. It is currently the fourth cause of death among cancers in the western world. Unfortunately, systemic chemotherapy still relies on just a few drugs which until now have produced unsatisfactory results. Gemcitabine (2′-2′-difluorodeoxycytidine) is currently the standard chemotherapy treatment at all stages of pancreatic adenocarcinoma. Survival benefit and clinical impact however remain moderate due to a high degree of intrinsic and acquired resistance. Autophagy plays an important role in cell death decision but can also protect cells from various apoptotic stimuli. We investigated the function of autophagy in pancreatic carcinoma cells, which are frequently insensitive to standard chemotherapeutic agents. Here, we demonstrate that autophagy is one of the mechanisms responsible for the refractory response of pancreatic tumors to gemcitabine. We present evidence in vitro and in vivo that proves autophagy plays a protective role in pancreatic ductal carcinoma cells, preventing them from entering the apoptotic pathway after stimulus with gemcitabine, thus contributing to treatment resistance. A better understanding of the role in the process may help in the discovery of new strategies to overcome tumor drug resistance in this aggressive disease.
Therapeutic Targeting of Autophagy in Pancreatic Ductal Adenocarcinoma
Frontiers in Pharmacology
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by early metastasis, late detection, and poor prognosis. Progress towards effective therapy has been slow despite significant efforts. Novel treatment approaches are desperately needed and autophagy, an evolutionary conserved process through which proteins and organelles are recycled for use as alternative energy sources, may represent one such target. Although incompletely understood, there is growing evidence suggesting that autophagy may play a role in PDAC carcinogenesis, metastasis, and survival. Early clinical trials involving autophagy inhibiting agents, either alone or in combination with chemotherapy, have been disappointing. Recently, evidence has demonstrated synergy between the MAPK pathway and autophagy inhibitors in PDAC, suggesting a promising therapeutic intervention. In addition, novel agents, such as ONC212, have preclinical activity in pancreatic cancer, in part through autophagy inhibi...
Autophagy in Cancer Cell Death
Biology, 2019
Autophagy has important functions in maintaining energy metabolism under conditions of starvation and to alleviate stress by removal of damaged and potentially harmful cellular components. Therefore, autophagy represents a pro-survival stress response in the majority of cases. However, the role of autophagy in cell survival and cell death decisions is highly dependent on its extent, duration, and on the respective cellular context. An alternative pro-death function of autophagy has been consistently observed in different settings, in particular, in developmental cell death of lower organisms and in drug-induced cancer cell death. This cell death is referred to as autophagic cell death (ACD) or autophagy-dependent cell death (ADCD), a type of cellular demise that may act as a backup cell death program in apoptosis-deficient tumors. This pro-death function of autophagy may be exerted either via non-selective bulk autophagy or excessive (lethal) removal of mitochondria via selective mitophagy, opening new avenues for the therapeutic exploitation of autophagy/mitophagy in cancer treatment.
Cytotoxic Autophagy in Cancer Therapy
International Journal of Molecular Sciences, 2014
Autophagy is a process of cellular self-digestion, whereby the cell degrades subcellular materials in order to generate energy and metabolic precursors in order to prolong survival, classically under conditions of nutrient deprivation. Autophagy can also involve the degradation of damaged or aged organelles, and misfolded or damaged proteins to eliminate these components that might otherwise be deleterious to cellular survival. Consequently, autophagy has generally been considered a prosurvival response. Many, if not most chemotherapeutic drugs and radiation also promote autophagy, which is generally considered a cytoprotective response, in that its inhibition frequently promotes apoptotic cells death. Furthermore, it has been shown that conventional chemotherapeutic drugs and radiation alone rarely induce a form of autophagy that leads to cell death. However, there are multiple examples in the literature where newer chemotherapeutic agents, drug combinations or drugs in combination with radiation promote autophagic cell death. This review will describe autophagic cell death induced in breast tumor cells, lung cancer cells as well as glioblastoma, demonstrating that it cannot be concluded that stress induced autophagy is, of necessity, cytoprotective in function.
IEEE/ACM Transactions on Computational Biology and Bioinformatics, 2015
Pancreatic cancer is a highly aggressive and chemotherapy-resistant malignant neoplasm. In basal condition, it is characterized by elevated autophagy activity, which is required for tumor growth and that correlates with treatment failure. We analyzed the expression of autophagy related genes in different cell lines. A correlation-based network analysis evidenced the sociality and topological roles of the autophagy-related genes after serum starvation. Structural and functional tests identified a core set of autophagy related genes, suggesting different scenarios of autophagic responses to starvation, which may be responsible for the clinical variations associated with pancreatic cancer pathogenesis.