Mitochondrial Metabolism in PDAC: From Better Knowledge to New Targeting Strategies

Cancer cells reprogram their metabolism to meet bioenergetics and biosynthetic demands. The first observation of metabolic reprogramming in cancer cells was made a century ago (“Warburg effect” or aerobic glycolysis), leading to the classical view that cancer metabolism relies on a glycolytic phenotype. There is now accumulating evidence that most cancers also rely on mitochondria to satisfy their metabolic needs. Indeed, the current view of cancer metabolism places mitochondria as key actors in all facets of cancer progression. Importantly, mitochondrial metabolism has become a very promising target in cancer therapy, including for refractory cancers such as Pancreatic Ductal AdenoCarcinoma (PDAC). In particular, mitochondrial oxidative phosphorylation (OXPHOS) is an important target in cancer therapy. Other therapeutic strategies include the targeting of glutamine and fatty acids metabolism, as well as the inhibition of the TriCarboxylic Acid (TCA) cycle intermediates. A better knowledge of how pancreatic cancer cells regulate mitochondrial metabolism will allow the identification of metabolic vulnerabilities and thus novel and more efficient therapeutic options for the benefit of each patient.

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Novel Liver X Receptor Ligand GAC0001E5 Disrupts Glutamine Metabolism and Induces Oxidative Stress in Pancreatic Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21249622 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9622

Author(s):

Shivangi Srivastava ◽

Scott Widmann ◽

Charles Ho ◽

Donovan Nguyen ◽

Alexis Nguyen ◽

...

Keyword(s):

Oxidative Stress ◽

Pancreatic Cancer ◽

Cancer Cells ◽

Cancer Metabolism ◽

Target Genes ◽

Metabolic Reprogramming ◽

Glutamine Metabolism ◽

Ductal Adenocarcinoma ◽

Clinical Samples ◽

Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer with a high mortality rate due to the lack of early detection and effective treatment options for advanced diseases. Metabolic reprogramming, a common hallmark of malignant transformation in pancreatic cancer, is critical for the growth and survival of cancer cells and a potential target mechanism for the treatment of pancreatic cancer. PDAC cells have upregulated glutamine metabolism to meet their biosynthetic and oxidative demands. Liver X receptors (LXRs) are ligand-dependent transcription factors involved in maintaining metabolic homeostasis. LXRs regulate critical cancer-related processes and pathways, including cholesterol, glucose and lipid metabolism, and inflammatory and immune responses. Analysis of transcriptomic data from PDAC clinical samples reveals overexpression of LXRs and their target genes in tumors as compared to normal tissue controls. Targeting LXRs with the novel LXR inverse agonist and degrader GAC0001E5 inhibited PDAC cell proliferation. Using a metabolomics approach, we discovered that 1E5 inhibits glutamine anaplerosis and induces oxidative stress, which are detrimental to PDAC cells. These findings highlight a novel role for LXR in regulating cancer metabolism and the potential application of LXR modulators in targeting cancer metabolism in pancreatic cancer and other malignancies.

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NR5A2 transcriptional activation by BRD4 promotes pancreatic cancer progression by upregulating GDF15

Cell Death Discovery ◽

10.1038/s41420-021-00462-8 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Feng Guo ◽

Yingke Zhou ◽

Hui Guo ◽

Dianyun Ren ◽

Xin Jin ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Transcriptional Activation ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells ◽

Gene Sets ◽

And Migration

AbstractNR5A2 is a transcription factor regulating the expression of various oncogenes. However, the role of NR5A2 and the specific regulatory mechanism of NR5A2 in pancreatic ductal adenocarcinoma (PDAC) are not thoroughly studied. In our study, Western blotting, real-time PCR, and immunohistochemistry were conducted to assess the expression levels of different molecules. Wound-healing, MTS, colony formation, and transwell assays were employed to evaluate the malignant potential of pancreatic cancer cells. We demonstrated that NR5A2 acted as a negative prognostic biomarker in PDAC. NR5A2 silencing inhibited the proliferation and migration abilities of pancreatic cancer cells in vitro and in vivo. While NR5A2 overexpression markedly promoted both events in vitro. We further identified that NR5A2 was transcriptionally upregulated by BRD4 in pancreatic cancer cells and this was confirmed by Chromatin immunoprecipitation (ChIP) and ChIP-qPCR. Besides, transcriptome RNA sequencing (RNA-Seq) was performed to explore the cancer-promoting effects of NR5A2, we found that GDF15 is a component of multiple down-regulated tumor-promoting gene sets after NR5A2 was silenced. Next, we showed that NR5A2 enhanced the malignancy of pancreatic cancer cells by inducing the transcription of GDF15. Collectively, our findings suggest that NR5A2 expression is induced by BRD4. In turn, NR5A2 activates the transcription of GDF15, promoting pancreatic cancer progression. Therefore, NR5A2 and GDF15 could be promising therapeutic targets in pancreatic cancer.

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Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines

Cancers ◽

10.3390/cancers12020404 ◽

2020 ◽

Vol 12 (2) ◽

pp. 404 ◽

Cited By ~ 6

Author(s):

Guo ◽

Tan ◽

Chen ◽

Wang ◽

Feng

Keyword(s):

Chinese Medicine ◽

Cancer Therapy ◽

Traditional Chinese Medicine ◽

Cancer Cells ◽

Metabolic Pathways ◽

Cancer Metabolism ◽

Metabolic Reprogramming ◽

Traditional Chinese Medicines ◽

Chinese Medicines ◽

Incidence And Mortality

Cancer is a common and complex disease with high incidence and mortality rates, which causes a severe public health problem worldwide. As one of the standard therapeutic approaches for cancer therapy, the prognosis and outcome of chemotherapy are still far from satisfactory due to the severe side effects and increasingly acquired resistance. The development of novel and effective treatment strategies to overcome chemoresistance is urgent for cancer therapy. Metabolic reprogramming is one of the hallmarks of cancer. Cancer cells could rewire metabolic pathways to facilitate tumorigenesis, tumor progression, and metastasis, as well as chemoresistance. The metabolic reprogramming may serve as a promising therapeutic strategy and rekindle the research enthusiasm for overcoming chemoresistance. This review focuses on emerging mechanisms underlying rewired metabolic pathways for cancer chemoresistance in terms of glucose and energy, lipid, amino acid, and nucleotide metabolisms, as well as other related metabolisms. In particular, we highlight the potential of traditional Chinese medicine as a chemosensitizer for cancer chemotherapy from the metabolic perspective. The perspectives of metabolic targeting to chemoresistance are also discussed. In conclusion, the elucidation of the underlying metabolic reprogramming mechanisms by which cancer cells develop chemoresistance and traditional Chinese medicines resensitize chemotherapy would provide us a new insight into developing promising therapeutics and scientific evidence for clinical use of traditional Chinese medicine as a chemosensitizer for cancer therapy.

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Cancer metabolism and intervention therapy

Molecular Biomedicine ◽

10.1186/s43556-020-00012-1 ◽

2021 ◽

Vol 2 (1) ◽

Author(s):

Huakan Zhao ◽

Yongsheng Li

Keyword(s):

Cancer Cells ◽

Tumor Cells ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Acid Synthesis ◽

Pentose Phosphate ◽

Metabolic Reprogramming ◽

Cancer Therapies ◽

Proliferation And Metastasis ◽

Immunosuppressive Microenvironment

AbstractMetabolic reprogramming with heterogeneity is a hallmark of cancer and is at the basis of malignant behaviors. It supports the proliferation and metastasis of tumor cells according to the low nutrition and hypoxic microenvironment. Tumor cells frantically grab energy sources (such as glucose, fatty acids, and glutamine) from different pathways to produce a variety of biomass to meet their material needs via enhanced synthetic pathways, including aerobic glycolysis, glutaminolysis, fatty acid synthesis (FAS), and pentose phosphate pathway (PPP). To survive from stress conditions (e.g., metastasis, irradiation, or chemotherapy), tumor cells have to reprogram their metabolism from biomass production towards the generation of abundant adenosine triphosphate (ATP) and antioxidants. In addition, cancer cells remodel the microenvironment through metabolites, promoting an immunosuppressive microenvironment. Herein, we discuss how the metabolism is reprogrammed in cancer cells and how the tumor microenvironment is educated via the metabolic products. We also highlight potential metabolic targets for cancer therapies.

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The Crosstalk Between Cell Adhesion and Cancer Metabolism

International Journal of Molecular Sciences ◽

10.3390/ijms20081933 ◽

2019 ◽

Vol 20 (8) ◽

pp. 1933 ◽

Cited By ~ 16

Author(s):

Bárbara Sousa ◽

Joana Pereira ◽

Joana Paredes

Keyword(s):

Cell Adhesion ◽

Cancer Cells ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Redox Homeostasis ◽

Building Blocks ◽

Metabolic Reprogramming ◽

Special Focus ◽

Oncogenic Signaling ◽

Cell Cell

Cancer cells preferentially use aerobic glycolysis over mitochondria oxidative phosphorylation for energy production, and this metabolic reprogramming is currently recognized as a hallmark of cancer. Oncogenic signaling frequently converges with this metabolic shift, increasing cancer cells’ ability to produce building blocks and energy, as well as to maintain redox homeostasis. Alterations in cell–cell and cell–extracellular matrix (ECM) adhesion promote cancer cell invasion, intravasation, anchorage-independent survival in circulation, and extravasation, as well as homing in a distant organ. Importantly, during this multi-step metastatic process, cells need to induce metabolic rewiring, in order to produce the energy needed, as well as to impair oxidative stress. Although the individual implications of adhesion molecules and metabolic reprogramming in cancer have been widely explored over the years, the crosstalk between cell adhesion molecular machinery and metabolic pathways is far from being clearly understood, in both normal and cancer contexts. This review summarizes our understanding about the influence of cell–cell and cell–matrix adhesion in the metabolic behavior of cancer cells, with a special focus concerning the role of classical cadherins, such as Epithelial (E)-cadherin and Placental (P)-cadherin.

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mTOR Complexes as a Nutrient Sensor for Driving Cancer Progression

International Journal of Molecular Sciences ◽

10.3390/ijms19103267 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3267 ◽

Cited By ~ 16

Author(s):

Mio Harachi ◽

Kenta Masui ◽

Yukinori Okamura ◽

Ryota Tsukui ◽

Paul Mischel ◽

...

Keyword(s):

Amino Acid ◽

Cell Survival ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Cancer Metabolism ◽

Metabolic Reprogramming ◽

Cancer Cell Survival

Recent advancement in the field of molecular cancer research has clearly revealed that abnormality of oncogenes or tumor suppressor genes causes tumor progression thorough the promotion of intracellular metabolism. Metabolic reprogramming is one of the strategies for cancer cells to ensure their survival by enabling cancer cells to obtain the macromolecular precursors and energy needed for the rapid growth. However, an orchestration of appropriate metabolic reactions for the cancer cell survival requires the precise mechanism to sense and harness the nutrient in the microenvironment. Mammalian/mechanistic target of rapamycin (mTOR) complexes are known downstream effectors of many cancer-causing mutations, which are thought to regulate cancer cell survival and growth. Recent studies demonstrate the intriguing role of mTOR to achieve the feat through metabolic reprogramming in cancer. Importantly, not only mTORC1, a well-known regulator of metabolism both in normal and cancer cell, but mTORC2, an essential partner of mTORC1 downstream of growth factor receptor signaling, controls cooperatively specific metabolism, which nominates them as an essential regulator of cancer metabolism as well as a promising candidate to garner and convey the nutrient information from the surrounding environment. In this article, we depict the recent findings on the role of mTOR complexes in cancer as a master regulator of cancer metabolism and a potential sensor of nutrients, especially focusing on glucose and amino acid sensing in cancer. Novel and detailed molecular mechanisms that amino acids activate mTOR complexes signaling have been identified. We would also like to mention the intricate crosstalk between glucose and amino acid metabolism that ensures the survival of cancer cells, but at the same time it could be exploitable for the novel intervention to target the metabolic vulnerabilities of cancer cells.

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A Novel Therapeutic Target, BACH1, Regulates Cancer Metabolism

Cells ◽

10.3390/cells10030634 ◽

2021 ◽

Vol 10 (3) ◽

pp. 634

Author(s):

Joselyn Padilla ◽

Jiyoung Lee

Keyword(s):

Cancer Cells ◽

Cancer Patients ◽

Transcriptional Activation ◽

Pyruvate Dehydrogenase ◽

Therapeutic Target ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Mitochondrial Metabolism ◽

Pyruvate Dehydrogenase Kinase ◽

Migration And Invasion

BTB domain and CNC homology 1 (BACH1) is a transcription factor that is highly expressed in tumors including breast and lung, relative to their non-tumor tissues. BACH1 is known to regulate multiple physiological processes including heme homeostasis, oxidative stress response, senescence, cell cycle, and mitosis. In a tumor, BACH1 promotes invasion and metastasis of cancer cells, and the expression of BACH1 presents a poor outcome for cancer patients including breast and lung cancer patients. Recent studies identified novel functional roles of BACH1 in the regulation of metabolic pathways in cancer cells. BACH1 inhibits mitochondrial metabolism through transcriptional suppression of mitochondrial membrane genes. In addition, BACH1 suppresses activity of pyruvate dehydrogenase (PDH), a key enzyme that converts pyruvate to acetyl-CoA for the citric acid (TCA) cycle through transcriptional activation of pyruvate dehydrogenase kinase (PDK). Moreover, BACH1 increases glucose uptake and lactate secretion through the expression of metabolic enzymes involved such as hexokinase 2 (HK2) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) for aerobic glycolysis. Pharmacological or genetic inhibition of BACH1 could reprogram by increasing mitochondrial metabolism, subsequently rendering metabolic vulnerability of cancer cells against mitochondrial respiratory inhibition. Furthermore, inhibition of BACH1 decreased antioxidant-induced glycolysis rates as well as reduced migration and invasion of cancer cells, suggesting BACH1 as a potentially useful cancer therapeutic target.

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Activation of TAp73 and inhibition of thioredoxin reductase for improved cancer therapy inTP53 mutant pancreatic tumors

10.1101/398750 ◽

2018 ◽

Cited By ~ 1

Author(s):

Pilar Acedo ◽

Aristi Fernandes ◽

Joanna Zawacka-Pankau

Keyword(s):

Pancreatic Cancer ◽

Cancer Therapy ◽

Tumor Suppressor ◽

Cancer Cells ◽

Thioredoxin Reductase ◽

Genotoxic Stress ◽

Ductal Adenocarcinoma ◽

Pancreatic Tumors ◽

Pancreatic Cancer Cells ◽

Photodynamic Therapy Of Cancer

AbstractThe p73 is a tumor suppressor that compensates for p53 loss and induces apoptosis in tumors in response to genotoxic stress or small-molecule treatments.Pancreatic ductal adenocarcinoma (PDAC) has a late onset of the disease, responds poorly to the existing therapies and has very low overall survival rates.Here, using drug-repurposing approach, we found that protoporphyrin IX (PpIX) and benzoporphyrin derivative monoacid ring A (BPD) activate p73 and induce apoptosis in pancreatic cancer cells. PpIX and BPD induce reactive oxygen species and inhibit thioredoxin reductase 1 (TrxR1). Thus, PpIX and BPD target cancer cells’ vulnerabilities namely activate TAp73 tumor suppressor and inhibit oncogenic TrxR1. Our findings, may contribute to faster repurposing of PpIX and BPD to treat pancreatic tumors.Lay AbstractDespite the efforts, pancreatic cancer remains among the most aggressive tumors. Late diagnoses often linked with the asymptomatic disease progression make it extremely difficult to cure. We have used drugs that are already in clinics and applied in photodynamic therapy of cancer and showed that the compounds induce death of cancer cells. The mechanism is via activation of p73 tumor suppressor and inhibition oncogenic thioredoxin reductase. Molecules that in parallel induce two pathways leading to cell death might be very promising candidates for improved cancer therapy in pancreatic cancer patients.

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BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells

The Journal of Cell Biology ◽

10.1083/jcb.201701064 ◽

2017 ◽

Vol 216 (12) ◽

pp. 4091-4105 ◽

Cited By ~ 23

Author(s):

Ming-Xin An ◽

Si Li ◽

Han-Bing Yao ◽

Chao Li ◽

Jia-Mei Wang ◽

...

Keyword(s):

Glucose Metabolism ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Rna Binding ◽

Rna Binding Proteins ◽

Aerobic Glycolysis ◽

Ductal Adenocarcinoma ◽

Aberrant Expression ◽

Hexokinase 2 ◽

Pancreatic Cancer Cells

Aerobic glycolysis, a phenomenon known historically as the Warburg effect, is one of the hallmarks of cancer cells. In this study, we characterized the role of BAG3 in aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) and its molecular mechanisms. Our data show that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in PDAC cells. Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in glycolysis, at the posttranscriptional level. BAG3 interacted with HK2 mRNA, and the degree of BAG3 expression altered recruitment of the RNA-binding proteins Roquin and IMP3 to the HK2 mRNA. BAG3 knockdown destabilized HK2 mRNA via promotion of Roquin recruitment, whereas BAG3 overexpression stabilized HK2 mRNA via promotion of IMP3 recruitment. Collectively, our results show that BAG3 promotes reprogramming of glucose metabolism via interaction with HK2 mRNA in PDAC cells, suggesting that BAG3 may be a potential target in the aerobic glycolysis pathway for developing novel anticancer agents.

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DDR1-INDUCED NEUTROPHIL EXTRACELLULAR TRAPS DRIVE PANCREATIC CANCER METASTASIS

10.1101/2020.08.05.238097 ◽

2020 ◽

Author(s):

Jenying Deng ◽

Yaan Kang ◽

Chien-Chia Cheng ◽

Xinqun Li ◽

Bingbing Dai ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Cancer Metastasis ◽

Neutrophil Extracellular Traps ◽

Human Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Extracellular Traps ◽

Pancreatic Cancer Cells

AbstractPancreatic ductal adenocarcinoma (PDAC) tumors are characterized by a desmoplastic reaction and dense collagen that is known to promote cancer progression. A central mediator of pro-tumorigenic collagen signaling is the receptor tyrosine kinase discoid domain receptor 1 (DDR1). DDR1 is a critical driver of a mesenchymal and invasive cancer cell PDAC phenotype. Previous studies have demonstrated that genetic or pharmacologic inhibition of DDR1 prevents PDAC tumorigenesis and metastasis. Here, we investigated whether DDR1 signaling has cancer cell non-autonomous effects that promote PDAC progression and metastasis. We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs) and subsequent cancer cell invasion and metastasis. Moreover, we have identified that collagen-induced CXCL5 production was mediated by a DDR1-PKCθ-SYK-NFκB signaling cascade. Together, these results highlight the critical contribution of collagen I-DDR1 interaction in the formation of an immune microenvironment that promotes PDAC metastasis.SummaryDeng et al find that collagen signaling via DDR1 on human pancreatic cancer cells drives production and release of the cytokine, CXCL5, into systemic circulation. CXCL5 then triggers infiltration of neutrophils into the tumor where they promote cancer cell progression.

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