A lactate-induced Snail/STAT3 pathway drives GPR81 expression in lung cancer cells

Xie, Qiang; Zhu, Zhanzhan; He, Yuanpeng; Zhang, Zhijian; Zhang, Yao; Wang, Yixuan; Luo, Jincheng; Peng, Tianchou; Cheng, Feng; Gao, Jiguang; Cao, Yuxiang; Wei, Huijun; Wu, Zhihao

doi:10.1016/j.bbadis.2019.165576

Cited by 54 publications

(41 citation statements)

References 19 publications

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“…Although the impact of acidic microenvironment induced by lactate on tumorigenesis is well established, it has also become evident that lactate contributes to the tumor progression in many ways. In recent years, the studies from our lab and other labs has demonstrated that lactate plays a key role in immune evasion of cancer, this effect has been shown to be mediated in part through its ability to activate its receptor GPR81, which is highly expressed in cancer cells [ 13 , 16 , 38 , 39 ]. Furthermore, there is evidence of lactate as an alternative energy source to fuel oxidative tumor cells [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells

et al. 2020

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Background Metabolic reprogramming contributes significantly to tumor development and is tightly linked to drug resistance. The chemotherapeutic agent etoposide (VP-16) has been used clinically in the treatment of lung cancer but possess different sensitivity and efficacy towards SCLC and NSCLC. Here, we assessed the impact of etoposide on glycolytic metabolism in SCLC and NSCLC cell lines and investigated the role of metabolic rewiring in mediating etoposide resistance. Methods glycolytic differences of drug-treated cancer cells were determined by extracellular acidification rate (ECAR), glucose consumption, lactate production and western blot. DNA damage was evaluated by the comet assay and western blot. Chemoresistant cancer cells were analyzed by viability, apoptosis and western blot. Chromatin immunoprecipitation (ChIP) was used for analysis of DNA-protein interaction. Results Here we showed that exposure to chemotherapeutic drug etoposide induces an exacerbation of ROS production which activates HIF-1α-mediated the metabolic reprogramming toward increased glycolysis and lactate production in non-small cell lung cancer (NSCLC). We identified lactic acidosis as the key that confers multidrug resistance through upregulation of multidrug resistance-associated protein 1 (MRP1, encoded by ABCC1), a member of ATP-binding cassette (ABC) transporter family. Mechanistically, lactic acid coordinates TGF-β1/Snail and TAZ/AP-1 pathway to induce formation of Snail/TAZ/AP-1 complex at the MRP1/ABCC1 promoter. Induction of MRP1 expression inhibits genotoxic and apoptotic effects of chemotherapeutic drugs by increasing drug efflux. Furthermore, titration of lactic acid with NaHCO3 was sufficient to overcome resistance. Conclusions The chemotherapeutic drug etoposide induces the shift toward aerobic glycolysis in the NSCLC rather than SCLC cell lines. The increased lactic acid in extracellular environment plays important role in etoposide resistance through upregulation of MRP expression. These data provide first evidence for the increased lactate production, upon drug treatment, contributes to adaptive resistance in NSCLC and reveal potential vulnerabilities of lactate metabolism and/or pathway suitable for therapeutic targeting. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells

et al. 2020

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“…To date however, the use of pharmacological agents to block MCTs in cancer is contraindicated because of the ubiquitous expression of MCTs in most cell types and negative consequences for the host. Additionally, blocking or deleting HCAR-1 leads to a reduced transcription of cancer-regulated genes, thus diminishing cancer cell proliferation in animal and cell culture models (Brown et al, 2020;Xie et al, 2020). At present there are no definitive data indicating that aberrant lactate metabolism causes cancer, but it has been observed that lactate accumulation is associated with upregulation of cancer promoting genes and downregulation of cancer suppressor genes (San-Millan et al, 2020).…”

Section: Not a Few But Many Observersmentioning

confidence: 99%

Lactate in contemporary biology: a phoenix risen

Brooks

Arevalo

Osmond

et al. 2021

The Journal of Physiology

118

101

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After a Century, it's time to turn the page on understanding of lactate metabolism and appreciate that lactate shuttling is an important component of intermediary metabolism in vivo. Cell-Cell and intracellular Lactate Shuttles fulfill purposes of energy substrate production and distribution as well as cell signaling under fully aerobic conditions. Recognition of lactate shuttling came first in studies of physical exercise where the roles of driver (producer) and recipient (consumer) cells and tissues were obvious. Moreover, the presence of lactate shuttling as part of postprandial glucose disposal and satiety signaling has been recognized. Mitochondrial respiration creates the physiological sink for lactate disposal in vivo. Repeated lactate exposure from regular exercise results in adaptive processes such as mitochondrial biogenesis and other healthful circulatory and neurological characteristic such as improved physical work capacity, metabolic flexibility, learning, and memory. The importance of lactate and lactate shuttling in healthful living is further emphasized when lactate signaling and shuttling are dysregulated as occur in particular illnesses and injuries. Like a Phoenix, lactate has risen to major importance in 21 st Century Biology.

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“…binds to the GPR81 promoter to induce its expression (73). Interestingly, lactate-induced expression of GPR81 has been shown to trigger the tumor expression of the immune checkpoint ligand PD-L1, indicating an additional dimension of lactate-mediated immune dysregulation in the tumor milieu to dampen anti-tumor immunity (74), as will be discussed in the following section.…”

Section: Dysregulation Of Lactate Transport and Metabolic Symbiosismentioning

confidence: 99%

Lactate Metabolism and Immune Modulation in Breast Cancer: A Focused Review on Triple Negative Breast Tumors

Belič

Decock

2020

Front. Oncol.

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Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer associated with poor prognosis, early recurrence, and the lack of durable chemotherapy responses and specific targeted treatments. The recent FDA approval for immune checkpoint inhibition in combination with nab-paclitaxel for the treatment of metastatic TNBC created opportunity to advocate for immunotherapy in TNBC patients. However, improving the current low response rates is vital. Most cancers, including TNBC tumors, display metabolic plasticity and undergo reprogramming into highly glycolytic tumors through the Warburg effect. Consequently, accumulation of the metabolic byproduct lactate and extracellular acidification is often observed in several solid tumors, thereby exacerbating tumor cell proliferation, metastasis, and angiogenesis. In this review, we focus on the role of lactate acidosis in the microenvironment of glycolytic breast tumors as a major driver for immune evasion with a special emphasis on TNBCs. In particular, we will discuss the role of lactate regulators such as glucose transporters, lactate dehydrogenases, and lactate transporters in modulating immune functionality and checkpoint expression in numerous immune cell types. This review aims to spark discussion on interventions targeting lactate acidosis in combination with immunotherapy to provide an effective means of improving response to immune checkpoint inhibitors in TNBC, in addition to highlighting challenges that may arise from TNBC tumor heterogeneity.

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A lactate-induced Snail/STAT3 pathway drives GPR81 expression in lung cancer cells

Cited by 54 publications

References 19 publications

Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells

Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells

Lactate in contemporary biology: a phoenix risen

Lactate Metabolism and Immune Modulation in Breast Cancer: A Focused Review on Triple Negative Breast Tumors

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