The Monocarboxylate Transporter Inhibitor α-Cyano-4-Hydroxycinnamic Acid Disrupts Rat Lung Branching

Granja, Sara; Morais-Santos, Filipa; Miranda-Gonçalves, Vera; Viana-Ferreira, Manuel; Nogueira, Rosete; Nogueira‐Silva, Cristina; Correia‐Pinto, Jorge; Baltazar, Fátima

doi:10.1159/000356617

Cited by 18 publications

(13 citation statements)

References 51 publications

(67 reference statements)

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“…MCT1 and 4 have previously been described in the developing rat and human airway22. However, the expression of MCT1 declined as the lungs developed from the pseudoglandular to saccular phase indicating that, consistent with our observations, MCT1 is unlikely to be present in adult cells22.…”

Section: Discussionsupporting

confidence: 90%

Hyperglycaemia and Pseudomonas aeruginosa acidify cystic fibrosis airway surface liquid by elevating epithelial monocarboxylate transporter 2 dependent lactate-H+ secretion

Garnett

Kalsi

Sobotta

et al. 2016

Sci Rep

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The cystic fibrosis (CF) airway surface liquid (ASL) provides a nutrient rich environment for bacterial growth including elevated glucose, which together with defective bacterial killing due to aberrant HCO3− transport and acidic ASL, make the CF airways susceptible to colonisation by respiratory pathogens such as Pseudomonas aeruginosa. Approximately half of adults with CF have CF related diabetes (CFRD) and this is associated with increased respiratory decline. CF ASL contains elevated lactate concentrations and hyperglycaemia can also increase ASL lactate. We show that primary human bronchial epithelial (HBE) cells secrete lactate into ASL, which is elevated in hyperglycaemia. This leads to ASL acidification in CFHBE, which could only be mimicked in non-CF HBE following HCO3− removal. Hyperglycaemia-induced changes in ASL lactate and pH were exacerbated by the presence of P. aeruginosa and were attenuated by inhibition of monocarboxylate lactate-H+ co-transporters (MCTs) with AR-C155858. We conclude that hyperglycaemia and P. aeruginosa induce a metabolic shift which increases lactate generation and efflux into ASL via epithelial MCT2 transporters. Normal airways compensate for MCT-driven H+ secretion by secreting HCO3−, a process which is dysfunctional in CF airway epithelium leading to ASL acidification and that these processes may contribute to worsening respiratory disease in CFRD.

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Section: Discussionsupporting

confidence: 90%

Hyperglycaemia and Pseudomonas aeruginosa acidify cystic fibrosis airway surface liquid by elevating epithelial monocarboxylate transporter 2 dependent lactate-H+ secretion

Garnett

Kalsi

Sobotta

et al. 2016

Sci Rep

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“…48, 49 However, the most important biological functions of these two proteins are to supply carbohydrates and export the waste lactate to maintain cellular energy homeostasis. 50, 51, 52 …”

Section: Discussionmentioning

confidence: 99%

Oridonin induces autophagy via inhibition of glucose metabolism in p53-mutated colorectal cancer cells

Mai

Xie

et al. 2017

Cell Death Dis

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The Warburg effect is an important characteristic of tumor cells, making it an attractive therapeutic target. Current anticancer drug development strategies predominantly focus on inhibitors of the specific molecular effectors involved in tumor cell proliferation. These drugs or natural compounds, many of which target the Warburg effect and the underlying mechanisms, still need to be characterized. To elucidate the anticancer effects of a natural diterpenoid, oridonin, we first demonstrated the anticancer activity of oridonin both in vitro and in vivo in colorectal cancer (CRC) cells. Then miRNA profiling of SW480 cells revealed those intracellular signaling related to energy supply was affected by oridonin, suggesting that glucose metabolism is a potential target for CRC therapy. Moreover, our results indicated that oridonin induced metabolic imbalances by significantly inhibiting glucose uptake and reducing lactate export through significantly downregulating the protein levels of GLUT1 and MCT1 in vitro and vivo. However, the ATP level in oridonin-treated CRC cells was not decreased when oridonin blocked the glucose supply, indicating that oridonin induced autophagy process, an important ATP source in cancer cells. The observation was then supported by the results of LC3-II detection and transmission electron microscopy analysis, which confirmed the presence of autophagy. Furthermore, p-AMPK was rapidly deactivated following oridonin treatment, resulting in downregulation of GLUT1 and induction of autophagy in the cancer cells. Thus our finding helped to clarify the anticancer mechanisms of oridonin and suggested it could be applied as a glucose metabolism-targeting agent for cancer treatment.

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“…30,31 CD147 immunostaining was performed using a polymer system (UltraVision ONE Detection System: HRP Polymer Lab Vision Corporation) with primary antibody raised against CD147 (sc-71038, Santa Cruz Biotechnology), diluted 1:500, as previously described. 32 Colon carcinoma tissue was used as positive control for MCT1, MCT4, GLUT1 and CD147, while stomach was used for CAIX and kidney for MCT2. Tissue sections were counterstained with hematoxylin and permanently mounted.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Prognostic significance of monocarboxylate transporter expression in oral cavity tumors

et al. 2016

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The Monocarboxylate Transporter Inhibitor α-Cyano-4-Hydroxycinnamic Acid Disrupts Rat Lung Branching

Cited by 18 publications

References 51 publications

Hyperglycaemia and Pseudomonas aeruginosa acidify cystic fibrosis airway surface liquid by elevating epithelial monocarboxylate transporter 2 dependent lactate-H+ secretion

Hyperglycaemia and Pseudomonas aeruginosa acidify cystic fibrosis airway surface liquid by elevating epithelial monocarboxylate transporter 2 dependent lactate-H+ secretion

Oridonin induces autophagy via inhibition of glucose metabolism in p53-mutated colorectal cancer cells

Prognostic significance of monocarboxylate transporter expression in oral cavity tumors

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