scholarly journals Comparative Untargeted Metabolomic Profiling of Induced Mitochondrial Fusion in Pancreatic Cancer

Metabolites ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 627
Author(s):  
Nicholas Nguyen ◽  
Meifang Yu ◽  
Vinit Reddy ◽  
Ariana Acevedo-Diaz ◽  
Enzo Mesarick ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Metabolic Reprogramming ◽  
Model Systems ◽  
Ductal Adenocarcinoma ◽  
Cancer Growth ◽  
Common Pathway ◽  
Mitofusin 2 ◽  
Metabolomic Profiling

Mitochondria are dynamic organelles that constantly alter their shape through the recruitment of specialized proteins, like mitofusin-2 (Mfn2) and dynamin-related protein 1 (Drp1). Mfn2 induces the fusion of nearby mitochondria, while Drp1 mediates mitochondrial fission. We previously found that the genetic or pharmacological activation of mitochondrial fusion was tumor suppressive against pancreatic ductal adenocarcinoma (PDAC) in several model systems. The mechanisms of how these different inducers of mitochondrial fusion reduce pancreatic cancer growth are still unknown. Here, we characterized and compared the metabolic reprogramming of these three independent methods of inducing mitochondrial fusion in KPC cells: overexpression of Mfn2, genetic editing of Drp1, or treatment with leflunomide. We identified significantly altered metabolites via robust, orthogonal statistical analyses and found that mitochondrial fusion consistently produces alterations in the metabolism of amino acids. Our unbiased methodology revealed that metabolic perturbations were similar across all these methods of inducing mitochondrial fusion, proposing a common pathway for metabolic targeting with other drugs.

scholarly journals Comparative untargeted metabolomic profiling of induced mitochondrial fusion in pancreatic cancer

2021 ◽  
Author(s):  
Nicholas D. Nguyen ◽  
Meifang Yu ◽  
Vinit Y. Reddy ◽  
Ariana C. Acevedo-Diaz ◽  
Enzo C. Mesarick ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Metabolic Reprogramming ◽  
Model Systems ◽  
Ductal Adenocarcinoma ◽  
Cancer Growth ◽  
Common Pathway ◽  
Mitofusin 2 ◽  
Metabolomic Profiling

Mitochondria are dynamic organelles that constantly alter their shape through the recruitment of specialized proteins, like mitofusin-2 (Mfn2) and dynamin-related protein 1 (Drp1). Mfn2 induces the fusion of nearby mitochondria, while Drp1 mediates mitochondrial fission. We previously found that the genetic or pharmacological activation of mitochondrial fusion was tumor suppressive against pancreatic ductal adenocarcinoma (PDAC) in several model systems. The mechanisms of how these different inducers of mitochondrial fusion reduce pancreatic cancer growth are still unknown. Here, we characterized and compared the metabolic reprogramming of these three independent methods of inducing mitochondrial fusion in KPC cell: overexpression of Mfn2, genetic editing of Drp1, or treatment with leflunomide. We identified significantly altered metabolites via robust, orthogonal statistical analyses and found that mitochondrial fusion consistently produces alterations in the metabolism of amino acids. Our unbiased methodology revealed that metabolic perturbations were similar across all these methods of inducing mitochondrial fusion, proposing a common pathway for metabolic targeting with other drugs.

scholarly journals Organotypic Culture of Acinar Cells for the Study of Pancreatic Cancer Initiation

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2606
Author(s):  
Carlotta Paoli ◽  
Alessandro Carrer
Keyword(s):  
Pancreatic Cancer ◽  
Ex Vivo ◽  
Acinar Cells ◽  
Lineage Tracing ◽  
Metabolic Reprogramming ◽  
Pancreatic Acinar Cells ◽  
Ductal Adenocarcinoma ◽  
Molecular Features ◽  
The Impact

The carcinogenesis of pancreatic ductal adenocarcinoma (PDA) progresses according to multi-step evolution, whereby the disease acquires increasingly aggressive pathological features. On the other hand, disease inception is poorly investigated. Decoding the cascade of events that leads to oncogenic transformation is crucial to design strategies for early diagnosis as well as to tackle tumor onset. Lineage-tracing experiments demonstrated that pancreatic cancerous lesions originate from acinar cells, a highly specialized cell type in the pancreatic epithelium. Primary acinar cells can survive in vitro as organoid-like 3D spheroids, which can transdifferentiate into cells with a clear ductal morphology in response to different cell- and non-cell-autonomous stimuli. This event, termed acinar-to-ductal metaplasia, recapitulates the histological and molecular features of disease initiation. Here, we will discuss the isolation and culture of primary pancreatic acinar cells, providing a historical and technical perspective. The impact of pancreatic cancer research will also be debated. In particular, we will dissect the roles of transcriptional, epigenetic, and metabolic reprogramming for tumor initiation and we will show how that can be modeled using ex vivo acinar cell cultures. Finally, mechanisms of PDA initiation described using organotypical cultures will be reviewed.

scholarly journals Mitochondrial Fusion Suppresses Pancreatic Cancer Growth via Reduced Oxidative Metabolism

2018 ◽  
Author(s):  
Meifang Yu ◽  
Yanqing Huang ◽  
Amit Deorukhkar ◽  
Tara N. Fujimoto ◽  
Suman Govindaraju ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Oxidative Metabolism ◽  
Mitochondrial Fusion ◽  
Cancer Growth

scholarly journals HNF-1a promotes pancreatic cancer growth and apoptosis resistance via its target gene PKLR

2020 ◽  
Vol 52 (3) ◽  
pp. 241-250
Author(s):  
Zhiyao Fan ◽  
Kun Fan ◽  
Shengming Deng ◽  
Yitao Gong ◽  
Yunzhen Qian ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Target Gene ◽  
Malignant Tumors ◽  
Ductal Adenocarcinoma ◽  
Cancer Growth ◽  
Cancer Tissue ◽  
Apoptosis Resistance ◽  
Specific Expression ◽  
Pancreatic Cancer Cells

Abstract Pancreatic ductal adenocarcinoma is one of the deadliest malignant tumors, and many genes play important roles in its development. The hepatocyte nuclear factor-1a (HNF-1a) gene encodes HNF-1a, which is a transcriptional activator. HNF-1a regulates the tissue-specific expression of multiple genes, especially in pancreatic islet cells and in the liver. However, the role of the HNF-1a gene in the development of pancreatic cancer is still unclear. Here, we used immunohistochemical staining and real-time PCR to analyze HNF-1a expression in pancreatic cancer tissue. Stable cell lines with HNF-1a knockdown or overexpression were established to analyze the role of HNF-1a in pancreatic cancer cell proliferation and apoptosis by colony formation assay and flow cytometry. We also analyzed the L-type pyruvate kinase (PKLR) promoter sequence to identify the regulatory effect of HNF-1a on PKLR transcription and confirmed the HNF-1a binding site in the PKLR promoter via a chromatin immunoprecipitation assay. HNF-1a was found to be overexpressed in pancreatic cancer and promoted proliferation while inhibiting apoptosis in pancreatic cancer cells. PKLR was identified as the downstream target gene of HNF-1a and binding of HNF-1a at two sites in PKLR (−1931/−1926 and −966/−961) regulated PKLR transcription. In conclusion, HNF-1a is overexpressed in pancreatic cancer, and the transcription factor HNF-1a can promote pancreatic cancer growth and apoptosis resistance via its target gene PKLR.

scholarly journals Hepatocyte nuclear factor 1 alpha influences pancreatic cancer growth and metastasis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ramadevi Subramani ◽  
Joshua Medel ◽  
Kristina Flores ◽  
Courtney Perry ◽  
Adriana Galvez ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Immunohistochemical Analysis ◽  
Ductal Adenocarcinoma ◽  
Cancer Growth ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Pancreatic Cancer Cells ◽  
Pdac Tissue ◽  
Nuclear Factor 1

AbstractHepatocyte nuclear factor 1 homeobox alpha (HNF1α) is a transcription factor involved in endodermal organogenesis and pancreatic precursor cell differentiation and development. Earlier studies have reported a role for HNF1α in pancreatic ductal adenocarcinoma (PDAC) but it is controversial. The mechanism by which it impacts PDAC is yet to be explored in depth. In this study, using the online databases we observed that HNF1α is upregulated in PDAC, which was also confirmed by our immunohistochemical analysis of PDAC tissue microarray. Silencing HNF1α reduced the proliferative, migratory, invasive and colony forming capabilities of pancreatic cancer cells. Key markers involved in these processes (pPI3K, pAKT, pERK, Bcl2, Zeb, Snail, Slug) were significantly changed in response to alterations in HNF1α expression. On the other hand, overexpression of HNF1α did not induce any significant change in the aggressiveness of pancreatic cancer cells. Our results demonstrate that reduced expression of HNF1α leads to inhibition of pancreatic cancer growth and progression, which indicates that it could be a potential oncogene and target for PDAC.

scholarly journals Melatonin Affects Mitochondrial Fission/Fusion Dynamics in the Diabetic Retina

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Janet Ya-An Chang ◽  
Fei Yu ◽  
Liheng Shi ◽  
Michael L. Ko ◽  
Gladys Y.-P. Ko
Keyword(s):  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Neural Retina ◽  
Mitochondrial Fusion ◽  
Protein Marker ◽  
Mitofusin 2 ◽  
Atp Production ◽  
Beneficial Effects ◽  
Diabetic Retina ◽  
Retinal Microvasculature

Mitochondrial fission and fusion are dependent on cellular nutritional states, and maintaining this dynamics is critical for the health of cells. Starvation triggers mitochondrial fusion to maintain bioenergetic efficiency, but during nutrient overloads (as with hyperglycemic conditions), fragmenting mitochondria is a way to store nutrients to avoid waste of energy. In addition to ATP production, mitochondria play an important role in buffering intracellular calcium (Ca2+). We found that in cultured 661W cells, a photoreceptor-derived cell line, hyperglycemic conditions triggered an increase of the expression of dynamin-related protein 1 (DRP1), a protein marker of mitochondrial fission, and a decrease of mitofusin 2 (MFN2), a protein for mitochondrial fusion. Further, these hyperglycemic cells also had decreased mitochondrial Ca2+ but increased cytosolic Ca2+. Treating these hyperglycemic cells with melatonin, a multifaceted antioxidant, averted hyperglycemia-altered mitochondrial fission-and-fusion dynamics and mitochondrial Ca2+ levels. To mimic how people most commonly take melatonin supplements, we gave melatonin to streptozotocin- (STZ-) induced type 1 diabetic mice by daily oral gavage and determined the effects of melatonin on diabetic eyes. We found that melatonin was not able to reverse the STZ-induced systemic hyperglycemic condition, but it prevented STZ-induced damage to the neural retina and retinal microvasculature. The beneficial effects of melatonin in the neural retina in part were through alleviating STZ-caused changes in mitochondrial dynamics and Ca2+ buffering.

scholarly journals Epithelial Cell Transforming 2 (ECT2) is regulated by Yes-associated protein 1 (YAP1) and mediates pancreatic cancer progression and metastasis

2021 ◽  
Author(s):  
Ce Li ◽  
Zhenzi Peng ◽  
Yizhou Wang ◽  
Gloria Lam ◽  
Nicholas Nissen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Epithelial Cell ◽  
Mouse Model ◽  
Cancer Progression ◽  
Critical Role ◽  
Ductal Adenocarcinoma ◽  
Cancer Growth ◽  
Nucleotide Exchange ◽  
Poor Overall Survival ◽  
Cell Transforming

Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic and represents one of the deadliest forms of human cancers. Previous studies showed that activation of Yes-associated protein 1 (YAP1) plays a key role in malignant transformation in the pancreas. In this study, we found that YAP1 regulates the expression of epithelial cell transforming 2 (ECT2), a guanine nucleotide exchange factor for Rho-like GTPases. By immunohistochemistry analysis of human tissues, we show that ECT2 is highly expressed in primary PDAC and liver metastasis but not in normal pancreas. These correlations were also observed in a mouse model of PDAC, where pancreatic transformation is driven by mutants of Kras and Trp53. Notably, nuclear ECT2 is upregulated in the transition from pre-neoplastic lesions to PDAC. High levels of YAP1 or ECT2 expression correlates with poor overall survival rate of PDAC patients. We further demonstrate that ECT2 is required for pancreatic cancer cell proliferation and migration in vitro. Finally, using a syngeneic orthotopic xenograft mouse model for pancreatic cancer, we found that ablation of ECT2 expression reduces pancreatic cancer growth and dissemination to the liver. These findings highlight a critical role of ECT2 in promoting pancreatic cancer growth and metastasis and provides insights into development of novel methods for early detection and treatment.

Targeting Hedgehog in pancreatic cancer: An innovative approach but not for all tumors.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 205-205
Author(s):  
Kalliopi Andrikou ◽  
Luca Faloppi ◽  
Cristian Loretelli ◽  
Alessandra Mandolesi ◽  
Maristella Bianconi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Model Systems ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Hedgehog Signaling Pathway ◽  
Desmoplastic Reaction

205 Background: Exocrine pancreatic cancer is the fifth cause of cancer-related death in Europe and has a very poor prognosis for all disease stages. To date no medical treatment has significantly increased patients' survival. One of the reasons for pancreatic cancer's chemoresistance is the complex tumor architecture: cancer cells are surrounded by a dense desmoplastic stroma that blocks drugs delivery. Moreover, pancreatic cancer is characterized by a marked heterogeneity of cells, including cancer stem cells (CSCs) that act as tumor-initiating cells and hierarchically control the differentiated cancer cells. Recent studies in multiple pancreatic cancer model systems have implicated the Hedgehog signaling pathway in these tumor-stromal interactions. The Hedgehog signaling pathway, a crucial regulator of proliferation and differentiation during embryonic development, has been reported to be aberrant and SMO overexpression seems to be a mechanism of activation of this pathway in human pancreatic cancer fibroblasts. Several studies are ongoing to evaluate the potential role of Hedgehog inhibitors, we investigated the contribution of Hedgehog to pancreatic progression and aggressiveness, evaluating the associated of stemness and desmoplastic reaction. Methods: In 110 histological samples of pancreatic ductal adenocarcinoma were performed molecular biology assessment of SPARC, CD133, CD44, CD24, OCT3/4, SHH, IHH, DHH, SMO, PTCH1, PTCH2. Results: Our analysis showed a strictly correlation between overexpression of SMO and high levels of SPARC (p=0.0005) and stemness markers CD133 (p=0.04) and OCT3/4 (p=0.0023) Conclusions: Our data demonstrate a critical and conserved role of Hedgehog signaling in the regulation of stem cell lineages and in the determination of a pronounced desmoplastic reaction determining chemoresistance and disease progression. We can speculate that patients with an aggressive profile defined by SMO overexpression would be the best candidates for treatment with Hedgehog inhibitors. This evidence suggests that this pathway may hold promise for new therapeutic approaches.

scholarly journals Inhibition of mitochondrial dynamics preferentially targets pancreatic cancer cells with enhanced tumorigenic and invasive potential

2021 ◽  
Author(s):  
Sarah Courtois ◽  
Beatriz de Luxán-Delgado ◽  
Laure Penin-Peyta ◽  
Alba Royo-García ◽  
Beatriz Parejo-Alonso ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Energy Crisis ◽  
Ductal Adenocarcinoma ◽  
Expression Ratio ◽  
Pancreatic Cancer Cells ◽  
Cancer Aggressiveness

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors, partly due to its intrinsic aggressiveness, metastatic potential, and chemoresistance of the contained cancer stem cells (CSCs). Pancreatic CSCs strongly rely on mitochondrial metabolism to maintain their stemness, therefore representing a putative target for their elimination. Since mitochondrial homeostasis depends on the tightly controlled balance between fusion and fission processes, namely mitochondrial dynamics, we aimed to study this mechanism in the context of stemness. In human PDAC tissues, the mitochondrial fission gene DNM1L (DRP1) was overexpressed and positively correlated with the stemness signature. Moreover, we observed that primary human CSCs display smaller mitochondria and a higher DRP1/MFN2 expression ratio, indicating activation of mitochondrial fission. Interestingly, treatment with the DRP1 inhibitor mDivi-1 induced dose-dependent apoptosis, especially in CD133+ CSCs, due to accumulation of dysfunctional mitochondria and subsequent energy crisis in this subpopulation. Mechanistically, mDivi-1 inhibited stemness-related features, such as self-renewal, tumorigenicity and invasiveness, and chemosensitized the cells to the cytotoxic effects of Gemcitabine. In summary, mitochondrial fission is an essential process for pancreatic CSCs and represents an attractive target for designing novel multimodal treatments that will more efficiently eliminate cells with high tumorigenic potential.Simple SummaryDue to their intrinsic aggressiveness, cancer stem cells (CSCs) represent an essential target for the design of effective treatments against pancreatic cancer, one of the deadliest tumors. As pancreatic CSCs are particularly dependent on the activity of their mitochondria, we here focus on mitochondrial dynamics as a critical process in the homeostasis of these organelles. We found that pancreatic CSCs rely on mitochondrial fission, and its pharmacological inhibition by mDivi-1 resulted in the accumulation of dysfunctional mitochondria, provoking energy crisis and cell death in this subpopulation. Consequently, mDivi-1 blocked cellular functions related to cancer aggressiveness such as in vivo tumorigenicity, invasiveness and chemoresistance. Our data suggest that inhibition of mitochondrial fission represents a promising target for designing new multimodal therapies to fight pancreatic cancer.

scholarly journals Targeting Redox Metabolism in Pancreatic Cancer

2021 ◽  
Vol 22 (4) ◽  
pp. 1534
Author(s):  
Nadine Abdel Hadi ◽  
Gabriela Reyes-Castellanos ◽  
Alice Carrier
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Metabolism ◽  
Genetic Alterations ◽  
Metabolic Reprogramming ◽  
Antioxidant Defenses ◽  
Ductal Adenocarcinoma ◽  
Ros Production ◽  
High Concentration ◽  
Redox Metabolism

Cell metabolism is reprogrammed in cancer cells to meet their high bioenergetics and biosynthetic demands. This metabolic reprogramming is accompanied by alterations in redox metabolism, characterized by accumulation of reactive oxygen species (ROS). Elevated production of ROS, mostly by mitochondrial respiration, is counteracted by higher production of antioxidant defenses (mainly glutathione and antioxidant enzymes). Cancer cells are adapted to a high concentration of ROS, which contributes to tumorigenesis, metastasis formation, resistance to therapy and relapse. Frequent genetic alterations observed in pancreatic ductal adenocarcinoma (PDAC) affect KRAS and p53 proteins, which have a role in ROS production and control, respectively. These observations led to the proposal of the use of antioxidants to prevent PDAC development and relapse. In this review, we focus on the therapeutic strategies to further increase ROS level to induce PDAC cell death. Combining the promotion of ROS production and inhibition of antioxidant capacity is a promising avenue for pancreatic cancer therapy in the clinic.

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