Pancreatic cancer is frequently driven by oncogenic KRAS, the downstream signaling of which activates DRP1 and promotes mitochondrial fission . Nonetheless, some studies have revealed that OXPHOS is not consistently suppressed. Cieslak JA, ... Mechanistic insights into selective killing of OXPHOS-dependent cancer cells by arctigenin. Targeting OXPHOS. Therefore, concurrent inhibitions of the two pathways by nanomedicines may achieve synergistic effect to significantly promote energy deprivation of tumor compared with single metabolic inhibition. It gives the cancer cells a survival advantage in the hypoxic tumor microenvironment and protects them from cytotoxic effects of oxidative damage and apoptosis. OCR / ECAR Ratio (OXPHOS/Glycolytic) Experiment # 1 Experiment #2 Experiment #3 MCF-7 1.4 1.8 2.3 MCF-7R 2.5 proliferation2.0 1.9 ZR75.1 1.6 1.6 n.d. MDA-MB-231 0.36 0.86 1.1 MDA-MB-157 0.4 1.1 1.5 Invasiv MDA-MB-361 0.7 0.89 0.89 e Non-Invasive Discover requirements and drivers of cancer cell 0 100 200 300 400 500 600 700 800 900 1000 1100 Oxygen Consumption Rate Basal OCR (pmol/min) … Towards this end, we used CRISPR-Cas9 methodology to edit the endogenous locus of Dnm1l/Drp1 to ablate … By contrast, in normal cells, autophagy may not be a ected by the inhibition of ALDH because ATP is produced from OxPhos using NADH mainly supplied from the TCA cycle [13]. Inhibition of OXPHOS with a clinically applicable small molecule, IACS-010759, which targets complex I of the mitochondrial electron transport chain, results in marked growth inhibition in vitro and in vivo in ibrutinib-resistant patient-derived cancer models. The ineffectiveness of anti-PDAC therapies is believed to be due to the existence of a subpopulation of tumor cells known as cancer stem cells (CSCs), which are functionally plastic, and have exclusive tumorigenic, chemoresistant and metastatic capacities. Treatment of Pancreatic Cancer with Pharmacological Ascorbate. Indeed, increased OXPHOS has been observed in multiple cancer types, exemplifying that OXPHOS can also be utilized in oncogenic metabolism [8, 9]. Most of the other PDAC cell lines utilize OXPHOS for energy generation . Ashenafi Bulle, Jeroen Dekervel, Lise Deschuttere, David Nittner, Eric Van Cutsem, Chris Verslype, Jos van Pelt. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. Co-cultures of miR-21 overexpressing CAFs with pancreatic cancer cell lines promote tumor progression, whereas its downmodulation in CAFs inhibits glycolysis in these cells and disrupts the stroma-tumor metabolic crosstalk, thus preventing tumor progression . There is still no consensus on the metabolic characteristics of cancer stem cells, with several studies indicating that they are mainly glycolytic and others pointing instead to mitochondrial metabolism as their principal source of energy. In the present work we studied the mechanism of toxicity by arctigenin in the human pancreatic cell line, Panc-1, with special emphasis on the mitochondria. The majority of CAFs are derived from pancreatic stellate cells (PSCs), which are activated during carcinogenesis. Enhanced OXPHOS can facilitate PDAC cell growth . Also, the super-metastatic tumor cells obtained by experimental selection in vitro (SiHa-F3 cells) and in vivo (B16F10 and B16-M1 to M5 tumor cells) have increased OXPHOS with higher ROS production ( 20 ). MITF/PGC1α Axis in Melanoma. Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death, has a 5-year survival rate of approximately 7–9%. pancreatic ductal adenocarcinoma, high OXPHOS subtype mel-anoma, andendometrial carcinoma, and thatthiscanoccureven inthefaceofactiveglycolysis.OXPHOSinhibitorscouldtherefore be used to target cancer subtypes in which OXPHOS is upregu-lated and to alleviate therapeutically adverse tumor hypoxia. Alice Carrier's 10 research works with 19 citations and 552 reads, including: Targeting Mitochondrial Complex I Overcomes Chemoresistance in High OXPHOS Pancreatic Cancer The ineffectiveness of anti-PDAC therapies is believed to be due to the existence of a subpopulation of tumor cells known as cancer stem cells (CSCs), which are functionally plastic, and have exclusive tumorigenic, chemoresistant and metastatic capacities. Even so, a subset of metformin-resistant pancreatic CSCs can Table 1. Cancer is now viewed as a stem cell disease. Given that these cells are always located around blood vessels to perform aerobic metabolism, this raises the possibility of aerobic tumor cells, which tend to exhibit the reverse Warburg phenomenon. On the basis of PGC1α expression levels, melanomas have been defined into two subsets with different biologic phenotypes ().The PGC1α-positive cells exhibit elevated mitochondrial oxidative metabolism and substantial ROS detoxifying capacities. Here, we present evidence that normalizing the fragmented mitochondria of pancreatic cancer via the process of mitochondrial fusion reduces OXPHOS, which correlates with suppressed tumor growth and improved survival in preclinical models. Finally, considering cancer metabolic re-wiring towards OXPHOS and subsequent increased oxidative stress, we discuss ‘ferroptosis’, a ... we isolated xCT-KO clones from pancreatic cancer MIA PaCa2 cells that were grown in the presence of N-acetyl-Cysteine (NAC) to maintain intracellular cysteine and the glutathione pool (Fig. Whether disrupting mitochondrial fission would … Instead, it can be reactivated under some conditions, such as activation of the targeting OxPhos in cancer cells by inhibiting ALDH to reduce NADH production could selectively reduce the ATP level, causing selective inhibition of autophagy, leading to selective cancer cell death. fusion and suppresses OXPHOS Pancreatic cancer is frequently driven by oncogenic KRAS, whose downstream signaling activates DRP1 and promotes mitochondrial fission (10). Whether disrupting mitochondrial fission would have a therapeutic effect in pancreatic cancer was unknown. Fig. 32764982. Through an extensive medicinal chemistry campaign of lead optimization initially seeded with known modulators of HIF1α, Molina, Sun, and colleagues developed a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain: IACS-010759. Mitochondrial OXPHOS is abnormal in cancer cells, and many studies suggest that it may underlie tumor initiation, growth, and metastasis of cancer cells. For decades, tumor cells have been considered defective in mitochondrial respiration due to their dominant glycolytic metabolism. Mitochondrial fusion was achieved by genetic or pharmacologic inhibition of dynamin-related protein-1 (Drp1) or through overexpression of mitofusin … However, the mechanism of how arctigenin kills cancer cells is not fully understood. Cancer stem cells (CSCs) is a term that is borrowed from stem cells in normal tissues and referred to a subpopulation of high stemness and high tumorigenic tumor cells, which can regenerate the whole tumor after treatment. MD Anderson’s Institute of Applied Cancer Science is developing an OXPHOS inhibitor. A metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis—known as the Warburg effect—is characteristic for many cancers. However, a growing body of evidence is now challenging this assumption, and also implying that tumors are metabolically less homogeneous than previously supposed. OncoTargets and Therapy 2020, 13: 6907-6916. Brecht K1, Riebel V2, Couttet P2, Paech F1, Wolf A2, Chibout SD2, Pognan F2, Krähenbühl S1, Uteng M3. A subgroup of cancers including PDAC and lymphomas rely on mitochondrial metabolism. Meanwhile, pancreatic cancer stem cells rely on mitochondrial OXPHOS, which may be correlated with the suppression of MYC and the MYC/PGC-1α ratio, so mitochondrial agents and genetic therapy can easily target this phenotype . 29,31 Therefore, in the last 5 years, the metabolisms in pancreatic cancer has become a field of interest for research. Notably, pancreatic cancer stem cells (CSCs) are also strongly dependent on OXPHOS for self-renewal . Among all its functions, PGC1α-dependent regulation of OxPhos is best studied in cancer, especially in melanoma. However, adequate therapeutics are not currently available to target OXPHOS in cancer. 3A). It has also been shown that the surviving pancreatic cancer cells after doxycycline withdrawal depend on OXPHOS and are highly sensitive to OXPHOS inhibitors . 32 For instance, OXPHOS inhibition to treat cancers has gained more attention. [9][10][11] The pro-survival role of mitochondria in pancreatic cancer stem cells or dormant cells has been reported, 12,13 and OXPHOS is an emerging target in cancer therapy. However, pancreatic cancer cells display suppressed mitochondrial OXPHOS and increased glycolysis upon absorbing these exosomes . However, recent studies have shown that OXPHOS can be also upregulated in certain cancers, including leukemias, lymphomas, pancreatic ductal adenocarcinoma, high OXPHOS subtype melanoma, and endometrial carcinoma, and that this can occur even in the face of active glycolysis. Pancreatic cancer cells switch to a glycolytic phenotype. Herbal extract of three oriental herbs (H3) was tested on PANC-1 cell line of pancreatic cancer. Arctigenin has previously been identified as a potential anti-tumor treatment for advanced pancreatic cancer. Deoxyglucose is now evaluated in clinical trials as a treatment agent for different cancers, such as lung, breast, and pancreatic cancer (clinicaltrials.gov numbers NCT00096707, NCT00633087). A small subpopulation of slow-cycling cells endowed with tumorigenic potential and … Glycolysis:oxidative phosphorylation (OXPHOS) ratio is variable Bioenergetic Organization Oxidative rates are variable Bioenergetics relates to cancer proliferation and vulnerabilities Figure 2. Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death, has a 5-year survival rate of approximately 7-9%. OXPHOS is another promising metabolic target for CSCs. Myoferlin, by a not yet fully understood mechanism, allows an optimized OXPHOS activity in pancreatic and colon cancer cells. In pancreatic cancer, miR-21 is upregulated in stroma, in particular in CAFs. Cancer cells have been demonstrated to be capable of switching their metabolic pathways between glycolysis and OXPHOS to adapt to endogenous and exogenous metabolic challenges. In PDAC, across a panel of 30 pancreatic cancer cell lines, only 13% of cell lines predominantly rely on glycolysis. cancer vulnerabilities driving cancer cell progression and proliferation. Pancreatic cancer cells exhibit highly fragmented mitochondria , ... Genetic or pharmacological inhibition of mitochondrial fission promotes mitochondrial fusion and suppresses OXPHOS. 32-37 CSCs have been identified in multiple tumors, like tumors of hematopoietic system, breast, prostate, pancreas, colon, skin, and brain. Anti-Cancer Activity of Acriflavine as Metabolic Inhibitor of OXPHOS in Pancreas Cancer Xenografts. cancers Article ATP Production Relies on Fatty Acid Oxidation Rather than Glycolysis in Pancreatic Ductal Adenocarcinoma Jae-Seon Lee 1, Su-Jin Oh 1, Hyun-Jung Choi 1, Joon Hee Kang 1, Seon-Hyeong Lee 1, Ji Sun Ha 1, Sang Myung Woo 2, Hyonchol Jang 1, Ho Lee 3 and Soo-Youl Kim 1,* 1 Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Korea; Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death, has a 5-year survival rate of approximately 9% and is expected to become the second most lethal tumor by the year 2030. To date, many compounds have been designed to precisely target OXPHOS. 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