Dysregulated pH: A perfect storm for cancer progression
ABSTRACT Although cancer is a diverse set of diseases, cancer cells share a number of adaptive hallmarks. Dysregulated pH is emerging as a hallmark of cancer because cancers show a 'reversed' pH gradient with a constitutively increased intracellular pH that is higher than the extracellular pH. This gradient enables cancer progression by promoting proliferation, the evasion of apoptosis, metabolic adaptation, migration and invasion. Several new advances, including an increased understanding of pH sensors, have provided insight into the molecular basis for pH-dependent cell behaviours that are relevant to cancer cell biology. We highlight the central role of pH sensors in cancer cell adaptations and suggest how dysregulated pH could be exploited to develop cancer-specific therapeutics.
- SourceAvailable from: Dongdong Wu
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- "Cancer cells could effectively excrete intracellular acid into the surrounding environment to form an acidified tumor microenvironment, which promotes angiogenesis, facilitates tumor metastasis, suppresses the host immune system, and contributes to chemoresistance . Thus, a novel practical strategy that regulates cancer cell pH could be an effective approach to induce cancer cell death . Treatment with 400 µM GYY4137 (a slow-releasing H 2 S donor) for 5 days significantly increases "
ABSTRACT: Hydrogen sulfide (H2S) is the third gaseous signaling molecule that plays important roles in cancer biological processes. Recent studies indicate that H2S has both pro-cancer and anti-cancer effects. Endogenous H2S can exert pro-cancer functions through induction of angiogenesis, the regulation of mitochondrial bioenergetics, the acceleration of cell cycle progression, and anti-apoptosis mechanisms. Thus, the inhibition of the production of H2S in cancer cells may be a new cancer treatment strategy. In contrast to the pro-cancer effect of H2S, relatively high concentrations of exogenous H2S could suppress the growth of cancer cells by inducing uncontrolled intracellular acidification, inducing cell cycle arrest, and promoting apoptosis. Therefore, H2S donors and H2S-releasing hybrids could be designed and developed as novel anti-cancer drugs. In this review, the production and metabolism of H2S in cancer cells are summarized and the role and mechanism of H2S in cancer development and progression are further discussed. Copyright © 2015. Published by Elsevier Inc.Nitric Oxide 08/2015; DOI:10.1016/j.niox.2015.08.004 · 3.18 Impact Factor
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- "According to  , relatively high pH i fosters cell division and provides resistance to cell apoptosis. Hence (see ), higher pH i may cause a reentry of the cell into the mitotic phase or suppression of mitotic arrest. "
ABSTRACT: Cancer research is not only a fast growing field involving many branches of science, but also an intricate and diversified field rife with anomalies. One such anomaly is the consistent reliance of cancer cells on glucose metabolism for energy production even in a normoxic environment. Glycolysis is an inefficient pathway for energy production and normally is used during hypoxic conditions. Since cancer cells have a high demand for energy (e.g. for proliferation) it is somehow paradoxical for them to rely on such a mechanism. An emerging conjecture aiming to explain this behavior is that cancer cells preserve this aerobic glycolytic phenotype for its use in invasion and metastasis (see, e.g., Gatenby and Gillies (2004) , Racker (1976) ). We follow this hypothesis and propose a new model for cancer invasion, depending on the dynamics of extra- and intracellular protons, by building upon the existing ones. We incorporate random perturbations in the intracellular proton dynamics to account for uncertainties affecting the cellular machinery. Finally, we address the well-posedness of our setting and use numerical simulations to illustrate the model predictions.Nonlinear Analysis Real World Applications 04/2015; 22:176–205. DOI:10.1016/j.nonrwa.2014.08.008 · 2.34 Impact Factor
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- "However, many cancers have elevated expression or activity of proteins that facilitate increased pHi, including carbonic anhydrase 9 (Swietach et al., 2007), H + -ATPases (Martinez-Zaguilan et al., 1993; Sennoune et al., 2004; Hinton et al., 2009), the ubiquitously expressed Na + -H + exchanger NHE1 (McLean et al., 2000; Miraglia et al., 2005; Chiang et al., 2008; Yang et al., 2011) and the monocarboxylate transporter family members MCT1 and MCT4 (Pinheiro et al., 2010; Halestrap, 2013). Therapeutic targeting of these proteins to reduce H + efflux and lower pHi has been suggested for limiting cancer progression (Webb et al., 2011; Harguindey et al., 2013), based primarily on findings with xenograft models and isolated cells. Xenograft tumor growth is suppressed by inhibiting NHE1 (Lagarde et al., 1988; Yang et al., 2011) or MCT1 (Sonveaux et al., 2008; Colen et al., 2011) activity. "
ABSTRACT: Intracellular pH (pHi) dynamics is increasingly recognized as an important regulator of a range of normal and pathological cell behaviors. Notably, increased pHi is now acknowledged as a conserved characteristic of cancers and in cell models is confirmed to increases proliferation and migration as well as limits apoptosis. However, the significance of increased pHi for cancer in vivo remains unresolved. Using Drosophila melanogaster, we show that increased pHi is sufficient to induce dysplasia in the absence of other transforming cues and potentiates growth and invasion with oncogenic Ras. Using a genetically encoded biosensor we also confirm increased pHi in situ. Moreover, in Drosophila models and clonal human mammary cells we show that limiting H(+) efflux with oncogenic Raf or Ras induces acidosis and synthetic lethality. Further, we show lethality in invasive, primary tumor cell lines with inhibiting H(+) efflux. Synthetic lethality with reduced H(+) efflux and activated oncogene expression could be exploited therapeutically to restrain cancer progression while limiting off-target effects.eLife Sciences 03/2015; 4. DOI:10.7554/eLife.03270 · 8.52 Impact Factor