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Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: implications for cancer therapies.

ABSTRACT: Acidic pH is an important feature of tumor microenvironment and a major determinant of tumor progression. We reported that cancer cells upregulate autophagy as a survival mechanism to acidic stress. Inhibition of autophagy by administration of chloroquine (CQ) in combination anticancer therapies is currently evaluated in clinical trials. We observed in 3 different human cancer cell lines cultured at acidic pH that autophagic flux is not blocked by CQ. This was consistent with a complete resistance to CQ toxicity in cells cultured in acidic conditions. Conversely, the autophagy-inhibiting activity of Lys-01, a novel CQ derivative, was still detectable at low pH. The lack of CQ activity was likely dependent on a dramatically reduced cellular uptake at acidic pH. Using cell lines stably adapted to chronic acidosis we could confirm that CQ lack of activity was merely caused by acidic pH. Moreover, unlike CQ, Lys-01 was able to kill low pH-adapted cell lines, although higher concentrations were required as compared with cells cultured at normal pH conditions. Notably, buffering medium pH in low pH-adapted cell lines reverted CQ resistance. In vivo analysis of tumors treated with CQ showed that accumulation of strong LC3 signals was observed only in normoxic areas but not in hypoxic/acidic regions. Our observations suggest that targeting autophagy in the tumor environment by CQ may be limited to well-perfused regions but not achieved in acidic regions, predicting possible limitations in efficacy of CQ in antitumor therapies.

SUBMITTER: Pellegrini P

PROVIDER: S-EPMC3984580 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Identification of acidic extracellular pH-modulated genes

Project description:To investigate the genes that are modulated by acidic extracellular pH, we treated the mouse B16-BL6 cells with acidic medium and then analyzed them comprehensively by cDNA microarray.

2024-09-09 | GSE276124 | GEO

Chloroquine enhanced the anticancer capacity of VNP20009 by inhibiting autophagy.

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Acidic extracellular pH promotes activation of integrin ?(v)?(3).

Project description:Acidic extracellular pH is characteristic of the cell microenvironment in several important physiological and pathological contexts. Although it is well established that acidic extracellular pH can have profound effects on processes such as cell adhesion and migration, the underlying molecular mechanisms are largely unknown. Integrin receptors physically connect cells to the extracellular matrix, and are thus likely to modulate cell responses to extracellular conditions. Here, we examine the role of acidic extracellular pH in regulating activation of integrin ?(v)?(3). Through computational molecular dynamics simulations, we find that acidic extracellular pH promotes opening of the ?(v)?(3) headpiece, indicating that acidic pH can thereby facilitate integrin activation. This prediction is consistent with our flow cytometry and atomic force microscope-mediated force spectroscopy assays of integrin ?(v)?(3) on live cells, which both demonstrate that acidic pH promotes activation at the intact cell surface. Finally, quantification of cell morphology and migration measurements shows that acidic extracellular pH affects cell behavior in a manner that is consistent with increased integrin activation. Taken together, these computational and experimental results suggest a new and complementary mechanism of integrin activation regulation, with associated implications for cell adhesion and migration in regions of altered pH that are relevant to wound healing and cancer.

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Afforestation neutralizes soil pH.

Project description:Soil pH regulates soil biogeochemical processes and has cascading effects on terrestrial ecosystem structure and functions. Afforestation has been widely adopted to increase terrestrial carbon sequestration and enhance water and soil preservation. However, the effect of afforestation on soil pH is still poorly understood and inconclusive. Here we investigate the afforestation-caused soil pH changes with pairwise samplings from 549 afforested and 148 control plots in northern China. We find significant soil pH neutralization by afforestation-afforestation lowers pH in relatively alkaline soil but raises pH in relatively acid soil. The soil pH thresholds (TpH), the point when afforestation changes from increasing to decreasing soil pH, are species-specific, ranging from 5.5 (Pinus koraiensis) to 7.3 (Populus spp.) with a mean of 6.3. These findings indicate that afforestation can modify soil pH if tree species and initial pH are properly matched, which may potentially improve soil fertility and promote ecosystem productivity.

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Acidic extracellular pH induces autophagy to promote anoikis resistance of hepatocellular carcinoma cells via downregulation of miR-3663-3p.

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Identification of acidic extracellular pH-modulated genes

Project description:Identification of acidic extracellular pH-modulated genes

| PRJNA1154953 | ENA

Chronic autophagy is a cellular adaptation to tumor acidic pH microenvironments.

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| S-EPMC3749826 | biostudies-literature

Carbonic anhydrase IX is a pH-stat that sets an acidic tumour extracellular pH in vivo.

Project description:BackgroundTumour carbonic anhydrase IX (CAIX), a hypoxia-inducible tumour-associated cell surface enzyme, is thought to acidify the tumour microenvironment by hydrating CO2 to form protons and bicarbonate, but there is no definitive evidence for this in solid tumours in vivo.MethodsWe used 1H magnetic resonance spectroscopic imaging (MRSI) of the extracellular pH probe imidazolyl succinic acid (ISUCA) to measure and spatially map extracellular pH in HCT116 tumours transfected to express CAIX and empty vector controls in SCID mice. We also measured intracellular pH in situ with 31P MRS and measured lactate in freeze-clamped tumours.ResultsCAIX-expressing tumours had 0.15 pH-unit lower median extracellular pH than control tumours (pH 6.71 tumour vs pH 6.86 control, P?=?0.01). Importantly, CAIX expression imposed an upper limit for tumour extracellular pH at 6.93. Despite the increased lactate concentration in CAIX-expressing tumours, 31P MRS showed no difference in intracellular pH, suggesting that CAIX acidifies only the tumour extracellular space.ConclusionsCAIX acidifies the tumour microenvironment, and also provides an extracellular pH control mechanism. We propose that CAIX thus acts as an extracellular pH-stat, maintaining an acidic tumour extracellular pH that is tolerated by cancer cells and favours invasion and metastasis.

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Acidic extracellular pH promotes epithelial mesenchymal transition in Lewis lung carcinoma model.

Project description:BackgroundEpithelial mesenchymal transition (EMT) is thought to be an essential feature of malignant tumor cells when they spread into the stroma. Despite the extracellular acidity of tumor tissues, the effect of acidic extracellular pH (pH e ) on EMT in carcinoma models, including the Lewis lung carcinoma (LLC) model, remains unclear.MethodsHigh and low metastatic LLC variants were generated by repeated tail vein injection of metastatic cells. DMEM/F12 medium, which has been supplemented with 15 mM HEPES, 4 mM phosphoric acid, and 1 g/L NaHCO3 and adjusted to the desire pH with HCl or NaOH, was used for cell culture. EMT marker gene expression was determined by quantitative reverse transcription-polymerase chain reaction. Migration and invasion activities were analyzed by wound healing assay and the Boyden chamber assay through Matrigel®, respectively.ResultsLow metastatic variant LLCm1 cells showed a cobble-stone like morphology at pH e 7.4. At pH e 6.8, however, their morphology became fibroblastic, similar in shape to high metastatic variant LLCm4 cells. Steady state levels of matrix metalloproteinase-9 (Mmp9) mRNA were induced by acidic pH e , maximizing at pH 6.8, with the levels of Mmp9 mRNA higher in LLCm4 than in LLCm1 cells. Both variants showed decreased levels of E-cadherin and increased levels of vimentin at pH e 6.8. Acidic pH e also induced expression of mRNAs encoding the E-cadherin repressors, Zeb2, Twist1 and Twist2, as well as enhancing cell motility and in vitro invasion through Matrigel®.ConclusionsAcidic pH e can induce EMT in some types of carcinoma.

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CDC20 Knockdown and Acidic Microenvironment Collaboratively Promote Tumorigenesis through Inhibiting Autophagy and Apoptosis.

Project description:The reconstitution of the tumorigenesis process would shed light on the tumor development study and further drug selection strategies. To construct a tumorigenesis model and explore potential mechanism is of great importance. In our study, we observed that CDC20-knockdown cells cultured in acidic environment exhibited chromosomal instability and better survival ability. The tumorigenic metabolism transformation was confirmed through the increase of the extracellular acidification rate (ECAR) and decrease of the oxygen consumption rate (OCR) in CDC20-knockdown cells. After a long-term culture for 3-4 months, CDC20-knockdown cells in acidic medium showed a strong tumor formation ability by subcutaneous injection into mice that is similar to that of tumor cells. Meanwhile, transcriptome analysis of cells from different stages showed that stage D cells almost resembled the phenotype of immortal cancer cells. The oncogene accumulation laid a firm foundation in the development of the tumorigenesis process by suppressing autophagy and p53-induced apoptosis. Several autophage- and apoptosis-related genes showed inhibition during this tumorigenesis process. In summary, chromosomal instability induced by CDC20 knockdown and acidic microenvironment could collaboratively promote cell tumorigenesis through the downregulation of autophagy and apoptosis.

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