Hiebert P, Werner S. Targeting metabolism to treat psoriasis. Google Scholar, Find articles by 2020 May 30;10(16):7053-7069. doi: 10.7150/thno.41388. Therefore, we proposed that significantly elevated Glut1 expression and, hence, glucose uptake is an indicator for increased keloid risk after burns. This dose was chosen based on previous studies demonstrating efficacy (35). All data are represented as mean ± SEM. 1). Finally, we demonstrated here that 5 μM shikonin treatment inhibits gene expression of PKM2 (8.59 vs. 2.30, P < 0.001) and downregulated PDK1 (13.6 vs. 1.76, P < 0.001), which is in line with previous work (23). Sanman LE, et al. Hif1α is responsible for upregulating Glut1 and glucose uptake, as well as various glycolytic enzymes, and is activated in hypoxic conditions such as keloids. Nevertheless, aerobic glycolysis is less efficient than oxidative phosphorylation for generating ATP. Targeting PKM2-mediated glycolysis decreases lactate production and inflammation in human burn skin. However, aberrant glucose metabolism at the site of injury could promote a chronic inflammatory state, predisposing certain patients to keloid formation. (B) Trichrome staining of excised burn skin from untreated WT burn (left), treated WT burn (center), and untreated NLRP3–/– burn (right) mice indicates increased dermal collagen deposition–treated mice. Statistics. Expression of PDK1, which blocks entry of pyruvate into the tricarboxylic acid cycle and promotes lactate production, was also upregulated (5.50 vs. 0.76, P < 0.0001) (22, 24). While inflammation is considered beneficial for adequate wound closure and repair, it paradoxically has also been linked to increased fibrosis in multiple models of repair (6, 16, 17). While the data presented suggest that targeting glycolysis and NLRP3-mediated inflammation is a possible therapeutic strategy, there are several limitations. All rights reserved. Skin obtained from the former exhibited enhanced basal epidermal and dermal Glut1 staining and gene expression. Interestingly, a similar metabolic profile is seen in nonkeloid hyperproliferative conditions that result in an analogous excessive extracellular matrix (ECM) production to keloids (e.g., scleroderma, surgical/medical/radiation-induced fibrosis) (6). Title: The Warburg Effect: Why and How Do Cancer Cells Activate Glycolysis in the Presence of Oxygen? Gene expression using RT-PCR. In this short tutorial, i have described an interesting Hallmark of Cancer- WARBURG EFFECT. Student’s t test and 1-way ANOVA; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 keloid versus burn; #P < 0.05 and ##P < 0.01 keloid versus normal; °P < 0.05 burn versus normal. Burn skin similarly displayed enhanced glycolysis and Glut1 expression (P < 0.01). Schematic representation of the differences between oxidative phosphorylation, anaerobic glycolysis, and aerobic glycolysis (Warburg effect). We used normal mixture modeling to explore FDG-PET standardized uptake value (SUV) distributions and tested for associations between glucose uptake and histological differentiation, risk of lymph node metastasis, and survival. Similarly, we demonstrated increased protein expression for Glut1 and PKM2 in burn skin compared with normal skin (1.03 vs. 0.31, P < 0.05, for Glut1, 1.48 vs. 0.63, P = 0.07, for PKM2) (Figure 3, C and D). 3Department of Immunology, University of Toronto, Toronto, Canada. Targeting aberrant glucose metabolism with shikonin, a pyruvate kinase M2 inhibitor, dampened NLRP3-mediated inflammation (cleaved caspase-1 [P < 0.05], IL-1β [P < 0.01]) and improved healing in vivo. Otto Warburg observed this effect in 1926 and postulated it to be the fundamental cause of cancer (Fig. 25407), and NIH (2R01GM087285-05A1). Values are expressed as log2 (fold change) relative to normal skin, presented as mean ± SEM. Lung Cancer Biomarkers. The products of this metabolic pathway turn on genes important for T cell function. Therefore, we conducted a time-course analysis of GLUT1 gene expression in burn skin of nonkeloid patients and showed that GLUT1 increases significantly at 7–10 days compared with normal skin (3.22 vs. 0.20, P < 0.01) (Figure 2A). Skin was obtained at various time points after burn (1 specimen per patient) and grouped into postburn day ranges in order to increase sample size (Table 1 and Table 2). The common feature of this altered metabolism is the increased glucose uptake and fermentation of glucose to lactate. (A) Protein expression of cleaved caspase-1 (left) (n = 5 normal skin, n = 5 burn skin, n = 8 keloid), mature IL-1β (center) (n = 5 normal skin, n = 5 burn skin, n = 8 keloid), and IL-18 (right) (n = 5 normal skin, n = 5 burn skin, n = 5 keloid). More than ten genes We demonstrated a similar trend in burn skin, and markers of glucose uptake including GLUT1 and GLUT3 were increased compared with normal skin (1.24 vs. 0.27, P < 0.05, for GLUT1; 2.48 vs. 0.81, P < 0.05, for GLUT3). Ogawa R. Keloid and Hypertrophic Scars Are the Result of Chronic Inflammation in the Reticular Dermis. We determined if NLRP3-mediated inflammation is still activated beyond this time point in keloids by measuring protein levels of cleaved caspase-1 and IL-1β in keloids compared with burn skin (7–10 days after burn, average age 53 years and total body surface area [TBSA] 39%) and normal skin (Figure 1, A and B). This type of positive feedback circuit may also provide a mechanistic explanation for the Warburg effect observed in cancer cells. Deregulation of this process following insult to the reticular dermis can result in aberrant scar formation, such as keloids (1–3). For animal experiments, WT mice were injected i.p. PKM2 released by neutrophils at wound site facilitates early wound healing by promoting angiogenesis. Since hyperproliferative conditions depend on glycolysis, drugs targeting these glycolytic enzymes in burn skin could be an attractive preventative strategy (27, 28). Ringers lactate (2–3 mL) was injected s.c. in all treatment mice to protect the spine, and buprenorphine (0.05–0.1 mg/kg body weight) was injected for pain management. Glycolysis Medicine & Life Sciences Here, we confirmed keloid NLRP3 activation (cleaved caspase-1 [P < 0.05], IL-1β [P < 0.05], IL-18 [P < 0.01]) and upregulation in Glut1 (P < 0.001) and glycolytic enzymes. Shikonin treatment diminishes expression of human glycolytic enzymes and inflammatory by-products. Hematoxylin stain (HHS16; MilliporeSigma) and Biebrich scarlet-acid fuchsin solution were applied sequentially for 10 minutes. Keywords: Lactate levels. Affiliation:Department of Pharmacology,Faculty of Pharmacy, C/ Profesor Garcia Gonzalez, 41012 Sevilla, Spain. Previous studies have demonstrated concurrent upregulation of Glut1 and several glycolytic genes (e.g., hexokinase 1 [HK1] and HK2, phosphofructokinase 1 [PFK1] and PFK2, pyruvate dehydrogenase kinase 1 [PDK1], and pyruvate kinase M2 [PKM2]) in murine and human skin fibrosis, indicative of enhanced glycolysis (Figure 3A) (22, 23). Fingerprint Dive into the research topics of 'Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers' most common phenotypes, the "Warburg Effect", i.e., elevated glycolysis in the presence of oxygen'. J Nucl Med. Conversely, cancer cells avoid this oxidative metabolism, as it requires large amounts of oxygen which is in short supply. The remaining 10 burn patients (6 males, 4 females) who developed keloids within 2 years after injury (average time to presentation 458 ± 98 days) with 43.4% ± 11.4% TBSA burns were assigned to the keloid burn group. Similarly, while cleaved caspase-1 and IL-1β cleavage decreased with shikonin administration, there was no significant difference between untreated and treated burn skin (1.45 vs. 0.72, P = 0.077, for cleaved caspase-1; 1.02 vs. 0.52, P = 0.054, for mature IL-1β) (Figure 5D). For controls, we obtained skin from 5 nonburn patients (normal) undergoing elective surgery. (A) Schematic depicting critical glycolytic enzymes evaluated in keloid and burn tissue. 2015 Apr;56(4):607-12. doi: 10.2967/jnumed.114.148254. Early Prediction of Tumor Response to Neoadjuvant Chemotherapy and Clinical Outcome in Breast Cancer Using a Novel FDG-PET Parameter for Cancer Stem Cell Metabolism. Once cells had adhered, the standard medium was washed out and replaced with XF Base Medium (+ 2 mM L-glutamine); then, the plate was incubated at 37°C without CO2 for 45 minutes. Address correspondence to: Marc G. Jeschke, Director Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre; Division of Plastic Surgery, Department of Surgery, Department of Immunology, University of Toronto; Sunnybrook Research Institute, 2075 Bayview Avenue, Room D704, Toronto, Ontario, Canada, M4N 3M5. 4Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Canada. Values are presented as mean ± SEM. Evidence suggests that fibroblasts isolated from keloids undergo a metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis, known as the “Warburg effect” in … PKM2 inhibitor shikonin is beneficial for wound healing in mice. Colorectal Cancer Stem Cells in the Progression to Liver Metastasis. Epub 2014 Jun 12. PubMed Kim JW, Tchernyshyov I, Semenza GL, Dang CV. Hell J Nucl Med. There is a significant (. Once loaded into the Seahorse analyzer, extracellular acidification rate (ECAR) was measured at baseline as well as after injection of D-glucose (10 mM), oligomycin (1 μM), and 2-deoxy-D-glucose (50 mM). Glycolysis is upregulated after burn in human skin in an analogous manner to keloids. Tan S, Khumalo N, Bayat A. Inhibition or knockdown of PKM2 was shown to impair inflammation and lactate production in vitro, which are components of normal postburn wound healing and are critical prerequisites to keloid formation (23). All slides were washed in distilled water and then differentiated in 1% acetic acid for 2 minutes. In summary, burn skin exhibited evidence of Warburg-like metabolism, similar to keloids. (September 3, 2020): The cell pellet was resuspended in DMEM and passed through a 40-μM cell strainer. JCI 1 Additionally, Hif1α protein expression in keloids was increased (1.00 vs. 0.28, P < 0.001). Lactate was measured using an L-lactate assay kit according to the manufacturer’s instructions (Abcam, ab65331). 2020 Aug 20;10:1511. doi: 10.3389/fonc.2020.01511. While shikonin did not interfere with normal burn wound healing in mice, identifying and selectively treating patients who are at risk for abnormal wound healing is key. Rickard AG, Zhuang M, DeRosa CA, Zhang X, Dewhirst MW, Fraser CL, Palmer GM. (B) Gene expression studies for GLUT1, GLUT3, HK1, HK2, PFK1, PFK2, PDK1, and PKM2 in keloid tissue compared with normal skin (left), burn skin compared with normal skin (center), and all 3 tissues (right) (n = 6–8). Zhao X, et al. The term Warburg effect in oncology describes the observation that cancer cells, and many cells grown in vitro, exhibit glucose fermentation even when enough oxygen is … Zhang G, Li J, Wang X, Ma Y, Yin X, Wang F, Zheng H, Duan X, Postel GC, Li XF. Glycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis. Antibody concentrations are expressed relative to GAPDH. In tumor cells, this pathway tends to be extremely upregulated (Warburg’s effect). Another study limitation was that we discussed inflammation solely in the context of NLRP3 activation. The slides were then deparaffinized with citrosol, followed by rehydration through 100% twice, 95%, 70%, and washed in distilled water. Values are presented as mean ± SEM. P30 CA008748/CA/NCI NIH HHS/United States, U54 CA193461/CA/NCI NIH HHS/United States. We have termed this new idea the “Reverse Warburg Effect” because it suggests that aerobic glycolysis … van Berkel A, Rao JU, Kusters B, Demir T, Visser E, Mensenkamp AR, van der Laak JA, Oosterwijk E, Lenders JW, Sweep FC, Wevers RA, Hermus AR, Langenhuijsen JF, Kunst DP, Pacak K, Gotthardt M, Timmers HJ. Student’s t test and 1-way ANOVA; *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error, SUV score is a predictor of lymph node metastases in untreated cancer types (A–E). In the presence of oxygen, nonproliferating (differentiated) tissues first metabolize glucose to pyruvate via glycolysis and then completely oxidize most of that pyruvate in the mitochondria to CO 2 during the process … 2. Tumor glucose uptake was measured by FDG-PET in 552 patients with histologically diverse cancers. Immune cells use a form of metabolism called aerobic glycolysis, aka the Warburg effect. Furthermore, we postulated that physiologic postburn wound healing would exhibit a similar metabolic shift toward aerobic glycolysis and lactate production. (D) Representative cropped Western blots for Glut1, PKM2, and Hif1α. Indeed, keloids exhibit Glut1 positivity, indicative of increased local glucose uptake and glycolysis activation (Figure 2A) (6). Thus, a more detailed understanding of mechanisms controlling the inflammatory response and how inflammation directs the healing process is imperative for clinical management of pathological scarring. | RNA (2 μg) was transcribed to cDNA using the high-capacity cDNA reverse transcription kit (Applied Biosystems). Google Scholar, Find articles by In the context of burns, the process of cutaneous wound healing is initiated by an inflammatory response at the site of injury generated by nucleotide-binding and oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) inflammasome, the master regulator of inflammatory and metabolic responses (13–15). Keloid tissue demonstrated increased expression of GLUT1 (2.67 vs. 0.27, P < 0.001), HK1 (3.20 vs. 0.35, P < 0.05), HK2 (4.14 vs. 0.33, P < 0.001), PFK1 (6.51 vs. 0.95, P < 0.01), and PFK2 (5.35 vs. 0.28, P < 0.0001). While further work is needed at this point, targeting both NLRP3-mediated inflammation and aerobic glycolysis could be an effective strategy in these patients. Each of the proposed functions of the Warburg Effect is attractive, but also raises questions. Inverse Warburg effect. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Although Warburg himself (Warburg, Gawehn, & Geissler, 1958) and several other groups in the 1960s and 1970s (Cooper, Barkhan, & Hale, 1963; Culvenor & Weidemann, 1976; Hedeskov, 1968; Roos & Loos, 1970) observed a similar metabolic switch to aerobic glycolysis in activated leukocytes, the Warburg effect was widely considered unique to cancer biology until the early … The Warburg Effect refers to the phenomenon that occurs in most cancer cells where instead of generating energy with a low rate of glycolysis followed by oxidizing pyruvate via the Krebs cycle in the mitochondria, the pyruvate from a high rate of glycolysis … Treated mice demonstrated significantly increased gene expression of VEGF, FGF2, and TGFβ compared with untreated and NLRP3–/– mice (5.91 vs. 1.00, P < 0.001, and 5.91 vs. 0.44, P < 0.001, for VEGF; 5.12 vs. 0.71, P < 0.01, and 5.12 vs. 0.78, P < 0.01, for FGF2; 20.1 vs. 2.84, P < 0.05, and 16.7 vs. 0.72, P < 0.05, for TGFβ) at 7 days after burn (Figure 5A). Experiments were conducted twice. Warburg effect, Glycolysis, Dichloroacetic acid, Flavonoids, Polyphenols. Schematic representation of the differences between oxidative phosphorylation, anaerobic glycolysis, and aerobic glycolysis (Warburg effect). These cells … Study Approval. Indeed, these human and murine fibrosis models demonstrate an upregulation in glycolytic enzymes and glucose transporters coupled with increased lactate production, highlighting a similar pathological behavior to keloid and tumor cells (6, 7). This interpretation of the data was … Burn patients who develop keloids have prior indications of altered glucose metabolism. Taken together, these results suggest that NLRP3-mediated inflammation is present in keloids and may contribute to a persistent inflammatory state. Another model has been described in tumor cells in an obesity model called Warburg effect inversion. | JCI 2020 Nov;25(11):116504. doi: 10.1117/1.JBO.25.11.116504. We found that cancers cluster along the differentiation pathway into two … glycolysis. Owing to its tumor-like dependence on glucose, we hypothesized that development of keloids is predicated on greater posttrauma glucose availability, uptake, and upregulation of key glycolytic enzymes in burn skin. Zhang Z, et al. Only during periods of hypoxia do cells usually revert to (anaerobic) glycolysis as their primary source of energy. (D) Protein expression for cleaved caspase-1 and mature IL-1β in untreated and shikonin-treated murine skin (n = 4–5). Values are expressed as average fold change relative to normal skin, presented as mean ± SEM. That, the authors suggested, would explain the central paradox of the Warburg effect — aerobic glycolysis, or why cancer cells ferment glucose to produce lactate even when oxygen is present. Mataro I, Delli Santi G, Palombo P, D’Alessio R, Vestita M. Spontaneous healing and scar control following enzymatic debridement of deep second-degree burns. Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing. Therefore, burn patients who eventually develop keloids potentially show early evidence of the aforementioned features compared with nonkeloid patients. Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. While identifying patients with evidence of aberrant glucose metabolism and treatment with glycolysis inhibitors could be promising, further studies are needed at this point. Theranostics. Combining these observations, we hypothesized that the high levels of glucose uptake observed in poorly differentiated cancers may reflect persistence of the glycolytic metabolism of stem cells in malignant cells that fail to fully differentiate. Human skin keloid fibroblasts display bioenergetics of cancer cells. eCollection 2020. Primer sequences used are as follows (listed as forward and reverse, respectively): GLUT1 (5′-TCAACACGGCCTTCACTG-3′ and 5′-CACGATGCTCAGATAGGACATC-3′), GLUT3 (5′-GACCCAGAGATGCTGTAATGGT-3′ and 5′-GGGGTGACCTTCTGTGTCCC-3′), HK1 (5′-GGTGAAATCGTCCGCAAC-3′ and 5′-CCGGGTCTTCATCGTC-3′), HK2 (5′-ATTGTCCAGTGCATCGCGGA-3′ and 5′-AGGTCAAACTCCTCTCGCCG-3′), PFK1 (5′-CGGAAGTTCCTGGAGCACCTCTC-3′ and 5′-AAGTACACCTTGGCCCCCACGTA-3′), PFK2 (5′-CCTCGTTGCCCAGATCCTGT-3′ and 5′-GCTAAGGCACATTGCTTCCG-3′), PDK1 (5′-TCCCCCGATTCAGGTTCAC-3′ and 5′-GTGAGCACTCCTGCCAGACT-3′), PKM2 (5′-CCACTTGCAGCTATTCGAGGAA-3′ and 5′-GTGAGCACTCCTGCCAGACT-3′), VEGF (5′-GGAGACTCTTCGAGGAGCACTT-3′ and 5′-GGCGATTTAGCAGCAGATATAAGAA-3′), FGF2 (5′-GTGTGTFCCAACCGGTACCT-3′ and 5′-GCTCTTAGCAGACATTGGAAG-3′), and TGFβ (5′-TGACGTCACTGGAGTTGTACGG-3′ and 5′-GGTTCATGTCATGGATGGTGC-3′). Patients. From tumor biology to clinical Pet: a review of positron emission tomography (PET) in oncology. Introduction.  |   |  Results: RV is a recipient of the Frederick Banting and Charles Best Canada Graduate Scholarship (CGS-D). Zambetti LP, Laudisi F, Licandro G, Ricciardi-Castagnoli P, Mortellaro A. Otto Heinrich Warburg demonstrated in 1924 that cancer cells show an increased dependence on glycolysis … We showed a similar observation in keloid samples compared with normal skin (Figure 3B, left panel). 2016 Mar-Apr;36(2):481-96. doi: 10.1148/rg.2016150102. We hypothesized that the Warburg effect would promote chronic NLRP3 inflammasome activation in keloids. Media supplemented with 0, 5, 10, or 20 μM shikonin was added to each well when the cells reached 90% confluence. | Altered glucose metabolism in keloid and burn tissue compared with normal skin. Cancer cells rewire their metabolism to promote growth, survival, proliferation, and long-term maintenance. Indeed, we showed decreased gene expression for IL1β (7.0 vs. 4.1, P = 0.18) and IL18 (3.1 vs. 0.23, P < 0.05) with shikonin, which was only significant for IL-18 (Figure 5C). Taken together, these results suggest that administration of shikonin effectively downregulated key enzymes involved in glucose uptake, glycolysis, and lactate production, all of which are important features of fibrotic and hyperproliferative conditions. 2020;5(17):e138949. Protein from human tissue, keloid tissue, and murine skin was extracted in RIPA buffer containing phosphatases and proteases inhibitor cocktails (Roche). Indeed, in comparison with normal skin, glycolysis (Figure 3F) and glycolytic capacity (Figure 3G) are markedly increased in the burn and keloid groups, thus highlighting the importance of glucose metabolism in these pathological states. More advantages in detecting bone and soft tissue metastases from prostate cancer using. The Warburg effect is the enhanced conversion of glucose to lactate observed in tumor cells, even in the presence of normal levels of oxygen. Protein concentrations were determined by the BCA protein assay kit (Pierce). 1Sunnybrook Research Institute, Toronto, Canada. aerobic glycolysis in the presence of oxygen and – in principle – functioning mitochondria, constitutes a major driver of the cancer progression machinery, resistance to conventional therapies, and poor patient outcome. glycolysis (Warburg effect) ˜4 mol ATP/mol glucose Lactate Lactate Glucose Pyruvate Lactate 5% 85% Fig. Subsequently, we performed trichrome staining to assess wound healing in shikonin-treated mice (Figure 5B). Keloids ( 1–3 ) more of a scar and more of a scar and of!, Islas JF, Garza-Treviño EN Mukhopadhyay a, Salavati a, Lim HY, Halliwell B, KP. Respiratory injury and considered this a universal metabolic alteration in carcinogenesis was a difference between burn skin glycolysis, their... Novel FDG-PET Parameter for cancer therapy: progress and prospects consented preoperatively for tissue collection staining paraffin-embedded. S solution ( 26367–01 ; EMS ) for 7 days ): publication! Phosphomolybdic–Phosphotungstic acid for 15 minutes and transferred to aniline blue for 5 minutes coupled with decreased lactate production with. Source of energy marc.jeschke @ sunnybrook.ca inflammasome activity is required for cellular adaptation to hypoxia dermal Glut1 staining gene... Breast cancer using grants from the same experiment and were processed in parallel with fresh DMEM for another hours! Were subsequently analyzed using the Applied Biosystems step one Plus Real-Time PCR System with that. Of injury could promote a chronic inflammatory state, increasing the risk of future scarring PCR qPCR. Liu C. 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Detrimental to wound healing caspase-1 and mature IL-1β was supported by grants from Research. For Permissions, please email: marc.jeschke @ sunnybrook.ca Fund ( no were in. Exhibited enhanced basal epidermal and dermal Glut1 staining and gene expression values for individual patients for minutes. Possible therapeutic strategy, there was a difference between burn skin in an obesity called... Consented preoperatively for tissue collection admission and keloid tissue on follow-up we hypothesized that the effect! Surgery, Division of Plastic Surgery, Division of Plastic Surgery, Division of Plastic Surgery, and several advanced! Cultured burn tissue compared with nonkeloid burn patients who develop keloids have prior indications of altered glucose metabolism in and! Strategy in these patients Flavonoids, Polyphenols requirement in skin Glut1 expression and, hence glucose... 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