Abstract
The hypoxic and acidic microenvironments in tumors are strongly associated with malignant progression and metastasis, and have thus become a central issue in tumor physiology and cancer treatment. Despite this, the molecular links between acidic pH- and hypoxia-mediated cell invasion/metastasis remain mostly unresolved. One of the mechanisms that tumor cells use for tissue invasion is the generation of invadopodia, which are actin-rich invasive plasma membrane protrusions that degrade the extracellular matrix. Here, we show that hypoxia stimulates the formation of invadopodia as well as the invasive ability of cancer cells. Inhibition or shRNA-based depletion of the Na+/H+ exchanger NHE-1, along with intracellular pH monitoring by live-cell imaging, revealed that invadopodia formation is associated with alterations in cellular pH homeostasis, an event that involves activation of the Na+/H+ exchange rate by NHE-1. Further characterization indicates that hypoxia triggered the activation of the p90 ribosomal S6 kinase (p90 RSK), which resulted in invadopodia formation and site-specific phosphorylation and activation of NHE-1. This study reveals an unsuspected role of p90RSK in tumor cell invasion and establishes p90RS kinase as a link between hypoxia and the acidic microenvironment of tumors.
Highlights
Recent research indicates that important metabolic changes occur within the tumor microenvironment and that these changes correlate with tumor progression and metastasis [1]
We showed that hypoxia promoted NHE-1 activity and its relocation to the basal plasma membrane where NHE-1-induced extracellular acidification leads to invadopodia production and cell invasion
We showed that the activity of NHE-1, but not its expression, was increased under hypoxia at times where we observed an enhancement in the generation of invadopodia
Summary
Recent research indicates that important metabolic changes occur within the tumor microenvironment and that these changes correlate with tumor progression and metastasis [1]. Hypoxia has been recognized as an important feature of solid tumors and arises presumably because of an increased metabolic demand associated with defective vascularization [2]. Hypoxia plays a critical role in various cellular events, including cell proliferation and metabolism, as well as tumor invasion and metastasis [3]. Similar to those prevailing in many tumors, have been shown to increase transcription of VEGF [12], of IL-8 [13,14], and to promote extracellular release/or expression/or activity of key proteases such as cathepsin B and matrix metalloproteinases (MMPs) [15]. Despite the physiological and clinical significance of the relationship between pH- and hypoxia-associated cell invasion and metastasis, this question remains largely unresolved
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