Abstract
Dysregulated intracellular pH is emerging as a hallmark of cancer. In spite of their acidic environment and increased acid production, cancer cells maintain alkaline intracellular pH that promotes cancer progression by inhibiting apoptosis and increasing glycolysis, cell growth, migration, and invasion. Here we identify signal transducer and activator of transcription-3 (STAT3) as a key factor in the preservation of alkaline cytosol. STAT3 associates with the vacuolar H+-ATPase in a coiled-coil domain-dependent manner and increases its activity in living cells and in vitro. Accordingly, STAT3 depletion disrupts intracellular proton equilibrium by decreasing cytosolic pH and increasing lysosomal pH, respectively. This dysregulation can be reverted by reconstitution with wild-type STAT3 or STAT3 mutants unable to activate target genes (Tyr705Phe and DNA-binding mutant) or to regulate mitochondrial respiration (Ser727Ala). Upon cytosolic acidification, STAT3 is transcriptionally inactivated and further recruited to lysosomal membranes to reestablish intracellular proton equilibrium. These data reveal STAT3 as a regulator of intracellular pH and, vice versa, intracellular pH as a regulator of STAT3 localization and activity.
Highlights
Tumorigenesis proceeds via an evolutionary process, in which a succession of genetic changes provide the transforming cells with a set of acquired capabilities that enable tumor growth and dissemination.[1]
signal transducer and activator of transcription-3 (STAT3) localizes to the lysosomal membrane Prompted by the punctate lysosome-like pattern of RFP-STAT3 in live A549 non-small cell lung cancer cells, in which the NH2 terminus of the endogenous STAT3 gene is tagged with a red fluorescent protein (RFP) using transcription activator-like effector nuclease-mediated knock-in,[34] we investigated the putative lysosomal localization and function of STAT3
The marker for endoplasmatic reticulum stained large parts of the cytoplasm and the resolution of confocal microscopy did not allow a proper analysis of its colocalization with RFP-STAT3 (Fig. 1a)
Summary
Tumorigenesis proceeds via an evolutionary process, in which a succession of genetic changes provide the transforming cells with a set of acquired capabilities that enable tumor growth and dissemination.[1] These traits include sustained proliferative signaling, metastatic capacity, activation of angiogenesis, replicative immortality, reprogrammed energy metabolism, as well as escape from cell death, growth suppressors, and immune destruction Besides these well-established hallmarks of cancer, the pH gradient reversal, i.e., acidification of extracellular pH (pHe) from ∼7.4 in normal cells to 6.5–7.0 in cancer cells, while maintaining alkaline cytosolic pH (pHc) of normal cells (∼7.2) or further alkalizing it to values as high as 7.6 in cancer cells, is emerging as a universal hallmark of cancer observed in malignant tumors regardless of the pathology, genetics, and origin.[2,3,4] The reversal of the pH gradient is an early event in tumorigenesis and its maintenance reinforces metabolic adaptation, tumor cell survival, invasion, immune evasion, and drug resistance. Most invasive cancer cells have an enlarged and highly acidic lysosomal compartment, more peripherally localized lysosomes, and an increase in lysosomal exocytosis.[11,12,13] the lysosomal V-ATPase may contribute to the establishment and maintenance of the reversed pH gradient of cancer cells by removing cytosolic protons to the lysosomal lumen, from where they can be effectively discarded to the extracellular space via lysosomal exocytosis
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