A critical role for autophagy in pancreatic cancer

Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Autophagy (Impact Factor: 11.75). 08/2011; 7(8):912-3. DOI: 10.4161/auto.7.8.15762
Source: PubMed
Autophagy is a regulated catabolic process that leads to the lysosomal degradation of damaged proteins, organelles and other macromolecules, with subsequent recycling of bioenergetic intermediates. The role of autophagy in cancer is undoubtedly complex and likely dependent on tumor type and on the cellular and developmental context. While it has been well demonstrated that autophagy may function as a tumor suppressor, there is mounting evidence that autophagy may have pro-tumorigenic roles, e.g., promoting therapeutic resistance as well as survival under stresses such as hypoxia and nutrient deprivation. These two, seemingly disparate functions can be reconciled by a possible temporal role of autophagy during tumor development, initially suppressing tumor initiation yet supporting tumor growth at later stages.

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    • "For pancreatic cancer, using IHC with an antibody specific for cleaved LC3, an important marker for monitoring autophagy, Yang et al. [38] found that there is a minimal cytoplasmic staining of cleaved LC3 in the normal pancreatic ductal epithelium and low-grade PanINs; however, the high-grade PanIN-3 and PDAC showed upregulated cleaved LC3 staining intensity. Combined with another review of Yang and Kimmelman [39], they suggest that, in the stage of tumor initiation, from PanIN-1 to PanIN-3 until PDAC, the ROS level and DNA damage are increased as well as autophagy. Autophagy would initially suppress tumor initiation by maintaining cellular homeostasis to counteract the ROS-mediated DNA damage. "
    [Show abstract] [Hide abstract] ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. Reactive oxygen species (ROS) are generally increased in pancreatic cancer cells compared with normal cells. ROS plays a vital role in various cellular biological activities including proliferation, growth, apoptosis, and invasion. Besides, ROS participates in tumor microenvironment orchestration. The role of ROS is a doubled-edged sword in pancreatic cancer. The dual roles of ROS depend on the concentration. ROS facilitates carcinogenesis and cancer progression with mild-to-moderate elevated levels, while excessive ROS damages cancer cells dramatically and leads to cell death. Based on the recent knowledge, either promoting ROS generation to increase the concentration of ROS with extremely high levels or enhancing ROS scavenging ability to decrease ROS levels may benefit the treatment of pancreatic cancer. However, when faced with oxidative stress, the antioxidant programs of cancer cells have been activated to help cancer cells to survive in the adverse condition. Furthermore, ROS signaling and antioxidant programs play the vital roles in the progression of pancreatic cancer and in the response to cancer treatment. Eventually, it may be the novel target for various strategies and drugs to modulate ROS levels in pancreatic cancer therapy.
    Full-text · Article · Jan 2016 · Oxidative medicine and cellular longevity
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    • "In addition to metabolic stress-activated autophagy , autonomous autophagy also plays a crucial role in tumor development. Recently, many studies have shown that several types of tumor cells require autonomous autophagy for tumor growth in normal condition [107,117]. "
    [Show abstract] [Hide abstract] ABSTRACT: Development of a tumor is a very complex process, and invasion and metastasis of malignant tumors are hallmarks and are difficult problems to overcome. The tumor microenvironment plays an important role in controlling tumor fate and autophagy induced by the tumor microenvironment is attracting more and more attention. Autophagy can be induced by several stressors in the tumor microenvironment and autophagy modifies the tumor microenvironment, too. Autophagy has dual roles in tumor growth. In this review, we discussed the interaction between autophagy and the tumor microenvironment and the paradoxical roles of autophagy on tumor growth at different stages of tumor development.
    Full-text · Article · Dec 2015 · Cell and Bioscience
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    • "Utilizing in vitro and clinically mimicking in vivo residual tumor models, the present study identified the autophagy-related molecular modulation that occurs after first-line radiotherapy, and further defined the clinical efficacy of high-polarity seaweed polyphenol fractions with demonstrated anti-PC potential. High basal autophagy in PC [18] is correlated with poor patient out- comes [19]. Intensified LC3 expression in PC tissue is associated with enhanced expression of carbonic anhydrase IX. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Identifying the drug-deliverables that target autophagy is crucial to finding a cure for pancreatic cancer (PC), as activated autophagy is associated with poor patient outcomes. Our recent studies recognized the anti-PC potential of an antioxidant-rich collection of seaweed polyphenols and identified potential compounds for the treatment of PC. Accordingly, we investigated whether such compounds could regulate autophagy in therapy-resistant PC cells in vitro and in residual PC in vivo. Results Human Panc-3.27 and MiaPaCa-2 cells were exposed to fractionated irradiation (FIR) with/without ethyl acetate (EA) polyphenol from Spatoglossum asperum (SA-EA), Padina tetrastromatica (PT-EA), or Hormophysa triquerta (HT-EA). The cells were subjected to QPCR to examine transcriptional alterations in the following autophagy functional regulators: ATG3, ATG5, ATG7, ATG12, LC3A, LC3B, Beclin, Myd88, HMGB1, Rage, and TLRs 1-9. Using a clinically relevant mouse model of residual PC, we use tissue microarray (TMA) and immunohistochemistry (IHC) procedures to investigate the potential of polyphenol(s) to target ATG3, ATG5, ATG12, LC3A, LC3B, BECN1, and SURIVIN after clinical radiotherapy. Radiation significantly increased the transcription of autophagy functional regulators in both cell lines. Seaweed polyphenols completely suppressed the transcription of all investigated autophagy regulators in both cell-lines. Gene silencing approach defined the role of LC3B in radiation-induced cell survival in this setting. TMA-IHC analysis revealed the complete regulation of ATG3, ATG5, ATG12, LC3A, LC3B, BECN1, and SURVIVIN in residual PC following SA-EA, PT-EA, and HT-EA treatment. Conclusions These data demonstrate the autophagy blue print in therapy-resistant PC cells for the first time. Moreover, the data strongly suggest that the selected polyphenols could serve as effective adjuvants for current PC treatment modalities and may inhibit tumor relapse by comprehensively targeting therapy-orchestrated autophagy in residual cells.
    Full-text · Article · Apr 2015 · Journal of Biomedical Science
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