乳酸代谢和乳酸抑制免疫细胞和HIF-乳酸-NDRG3信号通道研究
1. Pasteur Effect~present of oxygen stops glycolysis-fermentation of
glucose
2. Warburg Effect~cancer prefers aerobic glycolysis in the present of
oxygen-fermentation of glucose
3. Glucose is necessary for stabilization of hypoxia-inducible factor
4. LDHA-lowering
agent vitamin C
乳酸代谢和心肌
乳酸盐在心脏的新陈代谢中有两种既定的功能。首先，在有氧代谢过程中，乳酸盐是一种正常的心肌燃料，在一定的条件下(如运动)可以占心肌耗氧量的主要部分。乳酸的供应似乎取决于与其他心肌燃料的竞争，特别是游离脂肪酸。其次，在厌氧代谢过程中，乳酸的产生被认为是巴斯德效应的一部分，即厌氧菌病加速葡萄糖的摄取和糖酵解，而丙酮酸，而不是进入柠檬酸循环，形成乳酸。
Lactate Metabolism and Cardiac Muscle
Lactate has two established functions in the metabolism of the heart. First,
during aerobic metabolism lactate is a normal myocardial fuel, which during
certain conditions (e.g., exercise) can account for the major part of the
myocardial oxygen consumption. A supply of lactate appears to depend on
competition with other myocardial fuels, especially free fatty acids. Secondly,
during anaerobic metabolism, lactate production is viewed as part of the Pasteur
effect, whereby anaerobiosis accelerates glucose uptake and glycolysis, and
pyruvate, instead of entering the citrate cycle, forms lactate.
Lactate Metabolism and Cardiac Muscle | SpringerLink
https://link.springer.com/chapter/10.1007%2F978-3-642-67525-6_2
载体介导的大鼠肝细胞乳酸盐摄取。pH的影响及L -乳酸转运的可能机制
Fafournoux P, Demigne C, Remesy C。
摘要
研究了L-乳酸和d -乳酸在大鼠肝细胞制剂中的摄取率和胞内与胞外的分配比。L-和d
-乳酸的吸收明显依赖于被动扩散和载体介导的组分。L-乳酸高亲和载体的表观Km在1.8 mM范围内，乳酸同分异构体之间的相互竞争抑制表明L-乳酸和d
-乳酸可能通过不同的载体进行运输。不同阴离子抑制乳酸的转运;丙酮酸是最有效的阴离子，而只有高浓度的酮体才有效。酸性细胞外pH值增加乳酸盐的摄取，这种作用在l
-乳酸盐中更为明显。在低pH时，l
-乳酸被浓缩进入肝细胞，但其对载体的亲和力似乎没有改变，这表明存在一个从细胞膜上的pH梯度获取能量的过程。在乳酸/H+的假设中，H+的亲和力不依赖于乳酸浓度，H+的表观Km对应的pH值为7.34。在预先装载丙酮酸或乳酸盐的细胞后，未观察到乳酸盐摄取的反式刺激。目前的数据表明，在生理浓度下，肝脏对乳酸的吸收可能主要是通过载体介导的，肝细胞膜的转运速率可能与代谢速率相当。
Carrier-mediated uptake of lactate in rat hepatocytes. Effects of pH and
possible mechanisms for L-lactate transport.
Fafournoux P, Demigné C, Rémésy C.
Abstract
The rate of uptake and the distribution ratio between intra- and extracellular
compartments of L- and D-lactate were studied in hepatocyte preparations from
fed rats. L- and D-lactate uptake apparently depended on both passive diffusion
and carrier-mediated components. The apparent Km of the high-affinity carrier
for L-lactate was in the range of 1.8 mM. The reciprocal competitive inhibitions
between isomers of lactate suggest that L- and D-lactate might be transported by
distinct carriers. Lactate transport was inhibited by various anions; pyruvate
was the most potent anion, whereas only high concentrations of ketone bodies
were effective. Acidic extracellular pH enhanced lactate uptake, this effect
being more pronounced for L-lactate. At low pH, L-lactate was concentrated into
hepatocytes, but its affinity for the carrier appeared unchanged, suggesting the
existence of a process gaining energy from the pH gradient across the cell
membrane. In the hypothesis of a lactate/H+ symport, the affinity for H+ was not
dependent on lactate concentration and the apparent Km for H+ corresponded to a
pH of 7.34. No trans-stimulation of lactate uptake after prior loading of the
cells with pyruvate or lactate was observed. The present data suggest that, at
physiological concentrations, lactate uptake by the liver might be largely
carrier-mediated and the rate of transport across the liver cell membrane may be
of a magnitude relatively comparable to the rate of metabolism.
l-乳酸盐对大鼠脑神经元的吸收
摘要
用放射性示踪法研究了胚胎大鼠脑神经元原代培养对l-乳酸盐的吸收。细胞在无糖缓冲液中预孵育30分钟后，摄取随时间增加至少10分钟。在10mm乳酸处发现一个摄取饱和成分，半最大摄取。这个饱和组件被废除的10毫米α-cyano-4-hydroxycinnamic酸。此外，一种不饱和成分在高浓度的乳酸盐下主导吸收。随着pH值的降低，吸收速度加快，丙酮酸对其有明显的抑制作用。结果表明，神经元具有类似于外周组织的一元羧酸盐载体的乳酸转运系统。
Uptake of l-lactate by cultured rat brain neurons
Abstract
The uptake of l-lactate was investigated in neuronal primary cultures derived
from embryonic rat brain with a radioactive tracer method. After preincubation
of the cells in glucose-free buffer for 30 min, uptake increased with time for
at least 10 min. A saturable component of uptake was found with half-maximal
uptake at 10 mM lactate. This saturable component was abolished in the presence
of 10 mM α-cyano-4-hydroxycinnamic acid. In addition, a non-saturable component
dominated the uptake at high concentrations of lactate. Uptake was accelerated
with decreasing pH, and was inhibited considerably by pyruvate. It is concluded
that neurons are endowed with a lactate transport system which resembles in its
properties the monocarboxylate carrier of peripheral tissues.
肝细胞内细胞呼吸的氧气顺应性
细胞呼吸速率通常由代谢活动决定，但如果细胞氧张力(PO2)低于一个临界值(通常为1-10
Torr)，则呼吸速率将受到O2可用性的限制。降低代谢活动和能量需求以应对O2可用性下降的能力可能会增加对O2供应减少的抵抗力。原代培养的大鼠肝细胞在O2张力控制下被分离出来。用胶原酶消化法获得细胞，以相同的细胞密度接种于对照组和实验组的营养培养基中。当PO2快速减少(100→0
Torr > 40 min)时，细胞对O2的吸收未减少，直到PO2降低到10 Torr以下。相比之下，当细胞PO2在数小时内降低时，当O2张力达到70
Torr时，明显降低了对O2的吸收。这些下降与ATP浓度的降低和NAD(P)H的增加有关，而与同一PO2下的快速缺氧细胞相比。在PO2浓度降低24小时后，未检测到细胞活力的丧失。呼吸速率的降低与乳酸产量的增加有关。恢复正常氧与立即恢复到正常水平有关。这些结果表明，肝细胞能够通过一种机制，即除了氧气供应限制外，线粒体功能受到抑制，从而在PO2持续适度减少的过程中，可逆地降低代谢活动和氧气需求。这种反应可能改变细胞对包括缺氧在内的生理应激的敏感性。
Oxygen conformance of cellular respiration in hepatocytes
Cellular respiratory rates are normally determined by metabolic activity, but
become rate limited by O2 availability if the cell O2 tension (PO2) falls below
a critical value (typically 1-10 Torr). An ability to reduce metabolic activity
and energy demand in response to a falling O2 availability might confer an
increased resistance to a diminished O2 supply. Isolated rat hepatocytes were
studied in primary culture under controlled O2 tensions. Cells were obtained by
collagenase digestion and seeded into nutritive media in control and
experimental spinner flasks at identical cell densities. Cells subjected to
rapid reduction in PO2 (100 → 0 Torr over <40 min) exhibited undiminished O2
uptake until PO2 fell below 10 Torr. By contrast, when cell PO2 was reduced over
several hours, significant decreases in O2 uptake became evident at O2 tensions
as high as 70 Torr. These decreases were associated with a reduction in ATP
concentration and an increase in NAD(P)H, compared with rapidly deoxygenated
cells at the same PO2. No loss in cell viability was detected after 24 h at
reduced PO2. The decrease in respiratory rate was associated with an increased
rate of lactic acid production relative to normoxic controls. Restoration of
normoxia was associated with an immediate return of O2 uptake to control levels.
These results demonstrate that hepatocytes are capable of reversibly decreasing
metabolic activity and O2 demand during sustained moderate reductions in PO2,
via a mechanism that appears to involve an inhibition of mitochondrial function
other than O2 supply limitation. This response may alter cellular susceptibility
to physiological stresses including hypoxia.
Oxygen conformance of cellular respiration in hepatocytes — Northwestern
Scholars
https://www.scholars.northwestern.edu/en/publications/oxygen-conformance-of-cellular-respiration-in-hepatocytes
肿瘤细胞来源乳酸抑制人T细胞的活性
Inhibitory effect of tumor cell–derived lactic acid on human T cells
摘要
肿瘤的一个特征是由于糖酵解作用而产生大量乳酸。在此，我们展示了乳酸水平与肿瘤负荷之间的正相关关系，并在体外检测乳酸对免疫功能的影响。乳酸可抑制人细胞毒性T淋巴细胞(CTLs)的增殖和细胞因子的产生，抑制率高达95%，使细胞毒性活性降低50%。24小时无乳酸培养基恢复CTL功能。CTLs浸润产生乳酸的多细胞肿瘤球体后，细胞因子的产生降低。用乳酸产生抑制剂预处理肿瘤球状体可以防止这种效果。被激活的T细胞本身利用糖酵解和依赖乳酸的有效分泌，乳酸在细胞内积累扰乱了它们的新陈代谢。一元羧酸转运蛋白-1
(MCT-1)的输出依赖于细胞质和细胞外乳酸浓度之间的梯度，因此，阻断MCT-1会导致CTL功能受损。我们的结论是，肿瘤环境中的高乳酸浓度阻碍了T细胞中乳酸的输出，从而干扰了T细胞的代谢和功能。这些发现表明，在肿瘤中靶向这种代谢途径是增强肿瘤免疫原性的一种有前途的策略。
Inhibitory effect of tumor cell–derived lactic acid on human T cells
Abstract
A characteristic feature of tumors is high production of lactic acid due to
enhanced glycolysis. Here, we show a positive correlation between lactate serum
levels and tumor burden in cancer patients and examine the influence of lactic
acid on immune functions in vitro. Lactic acid suppressed the proliferation and
cytokine production of human cytotoxic T lymphocytes (CTLs) up to 95% and led to
a 50% decrease in cytotoxic activity. A 24-hour recovery period in lactic
acid–free medium restored CTL function. CTLs infiltrating lactic acid–producing
multicellular tumor spheroids showed a reduced cytokine production. Pretreatment
of tumor spheroids with an inhibitor of lactic acid production prevented this
effect. Activated T cells themselves use glycolysis and rely on the efficient
secretion of lactic acid, as its intracellular accumulation disturbs their
metabolism. Export by monocarboxylate transporter-1 (MCT-1) depends on a
gradient between cytoplasmic and extracellular lactic acid concentrations and
consequently, blockade of MCT-1 resulted in impaired CTL function. We conclude
that high lactic acid concentrations in the tumor environment block lactic acid
export in T cells, thereby disturbing their metabolism and function. These
findings suggest that targeting this metabolic pathway in tumors is a promising
strategy to enhance tumor immunogenicity.
Inhibitory effect of tumor cell–derived lactic acid on human T cells | Blood
Journal
http://www.bloodjournal.org/content/109/9/3812?sso-checked=true
缺氧时ndrg3介导的乳酸信号转导
摘要
缺氧与后生动物的许多病理状态和正常生理状态有关。我们发现在缺氧状态下，由氧和乳酸调节蛋白NDRG家族成员3
(NDRG3)介导的乳酸依赖信号通路。氧通过PHD2/VHL系统在蛋白水平负调控NDRG3的表达，而长期缺氧过量产生的乳酸通过与NDRG3结合阻断其蛋白酶体降解。我们还发现稳定的NDRG3蛋白通过激活raferk通路促进缺氧条件下的血管生成和细胞生长。抑制细胞内乳酸产生可消除ndrg3介导的缺氧反应。因此，ndrg3
- rafe -
erk轴为乳酸诱导的缺氧信号传导提供了遗传基础，这可用于针对缺氧诱导疾病的治疗方法的开发，以及促进我们对缺氧反应的正常生理机制的理解。[BMB报告2015;48
(6):301 - 302)
关键词:缺氧，乳酸信号，NDRG3, hif无关的缺氧反应，PHD2/VHL通路
低氧(缺氧)状态经常出现在正常生理的许多方面，如运动肌肉细胞或活跃生长的胚胎/胎儿组织。缺氧还与许多疾病如癌症和炎症密切相关。肿瘤患者缺氧与预后不良呈正相关。缺氧条件可诱导后生动物产生多种细胞反应，包括代谢重编程、血管生成和抗凋亡等，这些反应有助于后生动物对恶劣环境的适应和生存。缺氧诱导因子(HIFs)通过控制与缺氧反应不同方面相关的基因表达，在这些过程中起着中心作用。然而，越来越多的证据表明，缺氧有许多方面不能单独用hif介导的机制来解释。例如，hif介导通路的抑制并不总是阻止肿瘤的生长。此外，当HIF1A在胚胎干细胞或结肠癌细胞中被敲除时，血管生成被保留下来。因此，其他氧调节的途径，类似于HIF途径，由PHD酶控制的作用已经被提出。然而，低氧信号的hif无关方面仍然知之甚少。
利用免疫沉淀分析和质谱联用，我们发现了一种新的phd2结合蛋白，NDRG3，其表达通过蛋白酶体途径在蛋白水平上被氧负调控。我们发现NDRG3的善意衬底PHD2
/
VHL系统,特别是在294脯氨酸羟化(图1)。相比之下,积极NDRG3表达式是由乳酸,乳酸积累在缺氧的稍后阶段当绑定抑制NDRG3泛素化与VHL,随后通过破坏其交互块的蛋白酶体降解(图1)。然而,NDRG3并不依赖于低氧诱导因子mRNA表达的活动。
我们通过对NDRG3表达的细胞进行转录组分析，预测NDRG3在缺氧时的功能。然后，我们通过实验证明NDRG3通过促进细胞生长和血管生成，同时抑制缺氧诱导的细胞凋亡，在调节长时间缺氧反应中起关键作用。我们还发现，缺氧积累的NDRG3与c-Raf蛋白结合，诱导其磷酸化并激活下游ERK1/2信号通路。ndrg3介导的rafe
-
erk通路激活严重依赖于乳酸积累，这在细胞乳酸生产或通量是遗传或药物控制的实验中得到证实，或当乳酸外源提供给乳酸消耗细胞时也得到证实。此外，ndrg3介导的长时间缺氧的生物反应也依赖于乳酸积累和rafe
- erk通路的激活。
乳酸是糖酵解过程的最终产品,这是激活早期缺氧时HIF-1α让糖酵解基因表达诱导代谢适应。结果，在缺氧的后期，乳酸积累量增加。最近的研究报道了乳酸作为氧化性肿瘤的替代能源，作为血管生成的诱导剂，作为细胞运动的调节剂的不同作用。根据这些观察，高水平的乳酸生产和LDHA过表达被认为是癌症的负预后标志物。然而，调节乳酸诱导的生物反应的关键因素和潜在的分子机制仍然未知。
我们的研究结果证明了乳酸信号在缺氧中的作用及其遗传性质，这取决于ndrg3 -c- rafe - erk1
/2轴。这些发现表明,HIF-1α和NDRG3形成一种氧依赖性的监管链缺氧反应,分为两个时间阶段。在缺氧的早期阶段,HIF-1α蛋白积累,调节基因表达所必需的适应性反应包括早期代谢重编程,在后期阶段,差异乳酸生产积累NDRG3信号,激活Raf-ERK通路诱导反应所需应对长期缺氧。因此,乳酸信号和相应的生物反应似乎功能耦合HIF-1α-induced代谢重编程,采用NDRG3关键链接。在这方面,建议部分缺氧反应,特别是发生在缺氧的后阶段,迄今为止已归因于HIF-1α,可能,事实上,NDRG3-mediated乳酸直接控制下的信号。
综上所述，我们证明了NDRG3作为缺氧诱导的乳酸传感器，在促进缺氧反应中发挥了关键作用。NDRG3在缺氧乳酸信号传导中的作用表明，PHD2/VHL系统可以以依赖氧的方式控制hif依赖和非依赖的缺氧反应。因此,lactate-NDRG3-Raf-ERK信号通路可能提供延长机械的线索的理解障碍引起的突变VHL(成血管细胞瘤,肾细胞癌、嗜铬细胞瘤等)或PHD2(家族erythrocytosis-3)以及hypoxia-related生理(分化和发育、运动生理学等)和病理生理反应(癌症、伤口愈合、炎症、心血管疾病、高原反应,等等)。我们还认为，HIF和NDRG3的联合靶向可能是一种高效的抗缺氧策略，因为有证据表明，单纯抑制HIF可能不足以治疗缺氧诱导的疾病。
NDRG3-mediated lactate signaling in hypoxia
Abstract
Hypoxia is associated with many pathological conditions as well as the normal
physiology of metazoans. We identified a lactate-dependent signaling pathway in
hypoxia, mediated by the oxygen- and lactate-regulated protein NDRG family
member 3 (NDRG3). Oxygen negatively regulates NDRG3 expression at the protein
level via the PHD2/VHL system, whereas lactate, produced in excess under
prolonged hypoxia, blocks its proteasomal degradation by binding to NDRG3. We
also found that the stabilized NDRG3 protein promotes angiogenesis and cell
growth under hypoxia by activating the Raf-ERK pathway. Inhibiting cellular
lactate production abolishes NDRG3-mediated hypoxia responses. The NDRG3-Raf-ERK
axis therefore provides the genetic basis for lactate-induced hypoxia signaling,
which can be exploited for the development of therapies targeting
hypoxia-induced diseases in addition to advancing our understanding of the
normal physiology of hypoxia responses. [BMB Reports 2015; 48(6): 301-302]
Keywords: Hypoxia, Lactate signaling, NDRG3, HIF-independent hypoxia responses,
PHD2/VHL pathway
Low oxygen (hypoxia) conditions are frequently observed in many aspects of
normal physiology such as in cells of exercising muscle or actively growing
embryonic/fetal tissues. Hypoxia is also intimately associated with many
diseases such as cancer and inflammation. The presence of hypoxia has been
positively correlated with poor prognosis of cancer patients. Hypoxic conditions
induce various cellular responses in metazoans, including metabolic
reprogramming, angiogenesis, and anti-apoptosis, which facilitate adaptation to
and survival in the harsh environment. Hypoxia inducible factors (HIFs) play
central roles in these processes by controlling the expression of genes involved
in diverse aspects of hypoxia responses. However, growing evidence indicates
that hypoxia has many aspects that are not explained by HIF-mediated mechanisms
alone. For example, the inhibition of HIF-mediated pathways did not always
prevent tumor growth. Also, angiogenesis was preserved when HIF1A was
knocked-out in embryonic stem cells or colon cancer cells. Therefore, a role for
other oxygen-regulated pathways that are, similar to HIF pathways, controlled by
PHD enzymes has been suggested. However, the HIF-independent aspects of hypoxic
signaling remain poorly understood.
Using an immunoprecipitation assay coupled to mass spectrometry, we identified a
novel PHD2-binding protein, NDRG3, whose expression is negatively regulated by
oxygen at the protein level via the proteasomal pathway. We found that NDRG3 is
a bona fide substrate of the PHD2/VHL system, specifically hydroxylated at
proline 294 (Fig. 1). In contrast, NDRG3 expression is positively regulated by
lactate that accumulates at the later phase of hypoxia when lactate binding
inhibits NDRG3 ubiquitination by disrupting its interaction with VHL and
subsequently blocks the proteasomal degradation (Fig. 1). However, the mRNA
expression of NDRG3 was not dependent on HIF activity.
NDRG3-mediated lactate signaling in hypoxia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578614/
A Lactate-Induced Response to Hypoxia: Cell
https://www.cell.com/cell/fulltext/S0092-8674(15)00264-0
Overexpression of Pyruvate Kinase M2 in Tumor Tissues Is Associated with Poor
Prognosis in Patients with Hepatocellular Carcinoma | SpringerLink
https://link.springer.com/article/10.1007/s12253-019-00630-3
Overexpression of Pyruvate Kinase M2 in Tumor Tissues Is
Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, with
a high degree of malignancy and a poor prognosis. The aim of this study was to
investigate the relationship between expression of pyruvate kinase M2 (PKM2) and
prognosis in patients with HCC. The expression levels of PKM2 and PKM1 in 86
cases of HCC were detected by immunohistochemistry. An H score was used to
evaluate the expression of PKM, and all patients were further divided into PKM
high-expression and PKM low-expression groups. The relationship between PKM2
expression and the clinicopathological parameters and prognosis of patients were
subsequently analyzed. Our data suggested that the expression level of PKM2 was
significantly higher in HCC tissues than in adjacent tissues and the negatively
expression of PKM1 in HCC tissues. Kaplan-Meier analysis revealed that PKM2
expression was strongly associated with survival in HCC patients (P = 0.001).
The patients in the PKM2 high-expression group had significantly shorter
survival times than the patients in the PKM2 low-expression group (hazard ratio
for death, 2.358; 95% confidence interval [1.156, 4.812]; P = 0.018). In
conclusion, these data indicate that PKM2 expression in HCC tissue samples can
be used as a prognostic factor for patients with HCC and that high PKM2
expression is correlated with a poor prognosis in HCC patients.
Overexpression of Pyruvate Kinase M2 in Tumor Tissues Is Associated with Poor
Prognosis in Patients with Hepatocellular Carcinoma | SpringerLink
https://link.springer.com/article/10.1007/s12253-019-00630-3
Oncotarget | Overexpression of PKM2 promotes mitochondrial
fusion through attenuated p53 stability
M2-type pyruvate kinase (PKM2) contributes to the Warburg effect. However, it
remains unknown as to whether PKM2 has an inhibitory effect on mitochondrial
function. We report in this work that PKM2 overexpression inhibits the
expression of Drp1 and results in the mitochondrial fusion. The ATP production
was found to be decreased, the mtDNA copy number elevated and the expression
level of electron transport chain (ETC) complex I, III, V depressed in PKM2
overexpressed cells. PKM2 overexpression showed a decreased p53 protein level
and a shorter p53 half-life. In contrast, PKM2 knockdown resulted in increased
p53 expression and prolonged half-life of p53. PKM2 could directly bind with
both p53 and MDM2 and promote MDM2-mediated p53 ubiquitination. The dimeric PKM2
significantly suppressed p53 expression compared with the other PKM2 mutants.
The reverse relationship between PKM2 and Drp1 was further confirmed in a large
number of clinical samples. Taken together, the present results highlight a new
mechanism that link PKM2 to mitochondrial function, based on p53-Drp1 axis down
regulation, revealing a novel therapeutic target in patients with abnormal
mitochondria.
Oncotarget | Overexpression of PKM2 promotes mitochondrial fusion through
attenuated p53 stability
http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=12942&path%5B%5D=41000
ClinIcal Investigation. 2019 Mar 1;129(3):1030-1046. doi: 10.1172/JCI121685.
Epub 2019 Jan 28.
Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast
cancer stem-like cells.
Author information
1
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
2
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen
University, Guangzhou, China.
3
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian
Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
4
Center for Molecular Medicine, School of Life Science and Biotechnology, Dalian
University of Technology, Dalian, China.
5
Department of Oncology, The First Affiliated Hospital of Dalian Medical
University, Dalian, China.
6
Shanghai Information Center for Life Sciences, Shanghai Institutes for
Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
7
State Key Laboratory of Proteomics, National Center of Protein Sciences, Beijing
Institute of Lifeomics, Beijing, China.
8
Department of Molecular and Cellular Biochemistry, Markey Cancer Center,
University of Kentucky, College of Medicine, Lexington, Kentucky, USA.
9
Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences,
Shanghai, China.
10
Department of Surgery and Cancer, Imperial College London, London, United
Kingdom.
11
Laboratory of Immunophysiology, Department of Animal Sciences, College of
Agricultural, Consumer and Environmental Sciences, and Department of Pathology,
College of Medicine, University of Illinois at Urbana-Champaign, Urbana,
Illinois, USA.
Abstract
Chronic stress triggers activation of the sympathetic nervous system and drives
malignancy. Using an immunodeficient murine system, we showed that chronic
stress-induced epinephrine promoted breast cancer stem-like properties via
lactate dehydrogenase A-dependent (LDHA-dependent) metabolic rewiring. Chronic
stress-induced epinephrine activated LDHA to generate lactate, and the adjusted
pH directed USP28-mediated deubiquitination and stabilization of MYC. The SLUG
promoter was then activated by MYC, which promoted development of breast cancer
stem-like traits. Using a drug screen that targeted LDHA, we found that a
chronic stress-induced cancer stem-like phenotype could be reversed by vitamin
C. These findings demonstrated the critical importance of psychological factors
in promoting stem-like properties in breast cancer cells. Thus, the
LDHA-lowering agent vitamin C can be a potential approach for combating
stress-associated breast cancer.
临床调查。 2019三月1; 129（3）：1030-1046。 doi：10.1172 / JCI121685。 Epub 2019一月28。
应激诱导的肾上腺素增强乳酸脱氢酶A并促进乳腺癌干细胞样细胞。
作者信息
1个
大连医科大学肿瘤干细胞研究所，大连
2
中山大学肿瘤防治中心华南肿瘤学国家重点实验室，广州
3
中国科学院大连化学物理研究所，中国科学院分析化学分离科学重点实验室，中国大连。
4
大连理工大学生命科学与生物技术学院分子医学中心，大连
5
大连医科大学附属第一医院肿瘤科，大连。
6
中国科学院上海生物科学研究所上海生命科学信息中心，上海
7
北京生命科学研究院蛋白质组学国家重点实验室，蛋白质科学国家中心，北京。
8
美国肯塔基州列克星敦医学院，肯塔基大学马基癌症中心分子和细胞生物化学系。
9
复旦大学附属上海癌症中心和生物医学科学研究所，上海。
10
英国伦敦帝国理工学院，外科与癌症系。
11
美国伊利诺伊州厄巴纳-香槟分校，伊利诺伊大学，农业，消费者与环境科学学院，动物科学系，免疫科学实验室，病理学系。
摘要
慢性应激会触发交感神经系统的活化并引发恶性肿瘤。使用免疫缺陷的鼠类系统，我们表明，慢性应激诱导的肾上腺素通过乳酸脱氢酶A依赖性（LDHA依赖性）代谢重新布线促进了乳腺癌的茎状特性。慢性应激诱导的肾上腺素激活LDHA产生乳酸，调节后的pH值指导USP28介导的MYC去泛素化和稳定。然后，MYUG激活了SLUG启动子，从而促进了乳腺癌茎样性状的发展。使用针对LDHA的药物筛选，我们发现维生素C可以逆转慢性应激诱导的癌症茎样表型。这些发现证明了心理因素在促进乳腺癌细胞中茎样特性方面至关重要。因此，降低LDHA的维生素C可能是对抗与压力相关的乳腺癌的潜在方法。
应激诱导的肾上腺素增强乳酸脱氢酶A并促进乳腺癌干细胞样细胞。 -PubMed-NCBI
https://www.ncbi.nlm.nih.gov/pubmed/30688660
Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast
cancer stem-like cells. - PubMed - NCBI
https://www.ncbi.nlm.nih.gov/pubmed/30688660
Regeneron, Sanofi Cite Progress in Pursuing Eosinophilic Esophagitis Indication
for Dupixent
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