Dataset Information

Acidosis attenuates the hypoxic stabilization of HIF-1α by activating its lysosomal degradation

ABSTRACT: The adaptive responses to oxygen depletion orchestrated by hypoxia-inducible factors (HIFs) produce profound effects on multiple pathways. A canonical metabolic response is enhanced fermentation, but this can generate an unfavorably acidic environment under poor capillary perfusion. It is unclear how cells balance the metabolic benefits of hypoxic responses against knock-on consequences on acid-base homeostasis. We studied the interplay between hypoxia and acidosis on HIF signaling in colorectal cancer cell lines that can survive acidic conditions. Hypoxia stabilized HIF-1α, but this effect was transient in combination with acidosis. By 48 h, HIF-1α induction decreased in proportion to acidification. Proteomic analyses identified responses that followed HIF-1α, including canonical HIF targets (CA9, PDK1), but these did not reflect a proteome-wide downregulation. Responses to acidosis and hypoxia were enriched in lysosomal proteins, but not proteasomal components, implicating the former degradation pathway in transient HIF-1α activation under acidosis. Moreover, HIF-1α decay was not due to decreased HIF1A transcription but was blocked by lysosomal inactivation (bafilomycin-A1). Acidotic hypoxia increased the abundance of lysosomes and activated autophagy by disabling the inhibitory influence of mammalian target of rapamycin complex 1, resulting in HIF-1α degradation. By blocking HIF-driven fermentative upregulation, this mechanism protects the cellular environment from deleterious acid-overloading, an outcome that outweighs the biosynthetic benefits of raised glycolytic flux under suppressed respiration. Thus, alkaline conditions are permissive for at least some aspects of HIF-1α signaling, but may not reflect tumor microenvironment chemistry. Consequently, acidic hypoxic tumor regions may not necessarily overlay with sites of HIF induction

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Colorectal Cancer

SUBMITTER: Sarah Flannery

LAB HEAD: Iolanda Vendrell

PROVIDER: PXD062474 | Pride | 2025-06-30

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	OEA039_MSQ2911_PawelSwietach_CV-48_40spd_2T3_01_pH74-NO.raw	Raw
	OEA039_MSQ2911_PawelSwietach_CV-48_40spd_2T3_02_pH74-NO.raw	Raw
	OEA039_MSQ2911_PawelSwietach_CV-48_40spd_2T3_03_pH74-NO.raw	Raw
	OEA039_MSQ2911_PawelSwietach_CV-48_40spd_2T3_04_pH74-HY.raw	Raw
	OEA039_MSQ2911_PawelSwietach_CV-48_40spd_2T3_05_pH74-HY.raw	Raw

Items per page:

1 - 5 of 15

Publications

Acidosis attenuates the hypoxic stabilization of HIF-1α by activating lysosomal degradation.

White Bobby B Wang Zhenyi Z Dean Matthew M Michl Johanna J Nieora Natalia N Flannery Sarah S Vendrell Iolanda I Fischer Roman R Hulikova Alzbeta A Swietach Pawel P

The Journal of cell biology 20250624 8

Hypoxia-inducible factors (HIFs) mediate cellular responses to low oxygen, notably enhanced fermentation that acidifies poorly perfused tissues and may eventually become more damaging than adaptive. How pH feeds back on hypoxic signaling is unclear but critical to investigate because acidosis and hypoxia are mechanistically coupled in diffusion-limited settings, such as tumors. Here, we examined the pH sensitivity of hypoxic signaling in colorectal cancer cells that can survive acidosis. HIF-1α ...[more]

PMID: 40552983

Similar Datasets

Project description:Lactic acidosis and hypoxia are two prominent tumor microenvironmental stresses that are both known to exert important influences on gene expression and phenotypes of cancer cells. But very little is known about the cross-talk and interaction between these two stresses. We performed gene expression analysis of MCF7 cells exposed to lactic acidosis, hypoxia and combined lactic acidosis and hypoxia. We found the hypoxia response elicited under hypoxia was mostly abolished upon simultaneous exposure to lactic acidosis. The repression effects are due to loss of HIF-1Î± protein synthesis under lactic acidosis. In addition, we showed lactic acidosis strongly synergizes with hypoxia to activate the unfold protein response (UPR) and inflammation response which are highly similar to amino acid deprivation responses (AAR). The statistical factor analysis of hypoxia and lactic acidosis responses indicated that ATF4 locus, an important activator in the UPR/AAR pathway, is amplified in subsets of breast tumors and cancer cell lines. Varying ATF4 levels dramatically affect the ability to survive the post-stress recovery from hypoxia and lactic acidosis and may suggest its selection of ATF4 amplification in human cancers. These data suggest that lactic acidosis interacts with hypoxia by both inhibiting the canonical hypoxia response and while activating the UPR and inflammation response. Gain of ATF4 locus may offer survival advantages to allow successful adaptation to frequent fluctuations of oxygen and acidity in tumor microenvironment. Collectively, our studies have provided linkage between the short-term transcriptional responses to the long term selection of the DNA copy number alterations (CNAs) under tumor microenvironmental stresses. RNAs from MCF7 cells exposed to control condition (ambient air ~21% O2, no lactate and neutral pH), lactic acidosis (ambient air, 10 mM Lactate and pH 6.7), hypoxia (1% pO2, no lactate and neutral pH) and the combined lactic acidosis and hypoxia (1% pO2, 10 mM Lactate and pH 6.7) condition for 24 hours were extracted by miRVana kits (Ambion) and hybridized to Affymetrix Human genome 133A 2.0 arrays with standard protocol.