Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0847097 (acidity)
 15,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High expression of Cyr61, an extracellular cysteine-rich heparin-binding protein, has been associated with a malignant cell phenotype and poor outcome in prostate cancers. Although Cyr61 was found by us to be overproduced in androgen-independent PC-3 cells treated with N-acetylcysteine (NAC), its significance is still unclear. We therefore aimed to determine how and why Cyr61 protein is overexpressed in NAC-treated cells. Here, we found that Cyr61 protein level markedly increased in cells treated with NAC at high cell seeding density. Silencing of Cyr61 by siRNA induced enhanced activity of caspase-3/7, upregulation of the proapototic Bok, BimL and BimS, cleavage of apoptosis hallmarkers such as Bax, PARP and caspase-3, and downregulation of antiapoptotic Bcl2, Bcl-xL and Mcl-1 proteins. NAC treatment caused a reduction of extracellular medium pH to acidic and an increase in Akt phosphorylation, after which the replacement with NAC-free medium returned them to control levels within 24h. Acid stimulation increased the levels of Cyr61 and p-Akt proteins, whereas it suppressed the induction of proapoptotic and antiapoptotic proteins. Overall, our data indicate that PC-3 cells overproduce Cyr61 protein via activation of the PI3K/Akt signaling as a part of the survival mechanisms under the conditions causing extracellular acidity and further cytotoxicity.
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PMID:Production of Cyr61 protein is modulated by extracellular acidification and PI3K/Akt signaling in prostate carcinoma PC-3 cells. 2362 39

Proliferating cells reduce their oxidative metabolism and rely more on glycolysis, even in the presence of O2 (Warburg effect). This shift in metabolism reduces citrate biosynthesis and diminishes intracellular acidity, both of which promote glycolysis sustaining tumor growth. Because citrate is the donor of acetyl-CoA, its reduced production favors a deacetylation state of proteins favoring resistance to apoptosis and epigenetic changes, both processes contributing to tumor aggressiveness. Citrate levels could be monitored as an indicator of cancer aggressiveness (as already shown in human prostate cancer) and/or could serve as a biomarker for response to therapy. Strategies aiming to increase cytosolic citrate should be developed and tested in humans, knowing that experimental studies have shown that administration of citrate and/or inhibition of ACLY arrest tumor growth, inhibit the expression of the key anti-apoptotic factor Mcl-1, reverse cell dedifferentiation and increase sensibility to cisplatin.
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PMID:The reduced concentration of citrate in cancer cells: An indicator of cancer aggressiveness and a possible therapeutic target. 2818 97

Arctigenin, a mitochondrial complex I inhibitor, has been identified as a potential anti-tumor agent, but the involved mechanism still remains elusive. Herein, we studied the underlying mechanism(s) of action of arctigenin on acidity-tolerant prostate cancer PC-3AcT cells in the lactic acid-containing medium. At concentration showing no toxicity on normal prostate epithelial RWPE-1 and HPrEC cells, arctigenin alone or in combination with docetaxel induced significant cytotoxicity in PC-3AcT cells compared to parental PC-3 cells. With arctigenin treatment, reactive oxygen species (ROS) levels, annexin V-PE positive fractions, sub-G0/G1 peak in cell cycle analysis, mitochondrial membrane depolarization, and cell communication network factor 1 (CCN1) levels were increased, while cellular ATP content and phospho (p)-Akt level were decreased. Pretreatment with ROS scavenger N-acetylcysteine effectively reversed the series of phenomena caused by arctigenin, suggesting that ROS served as upstream molecules of arctigenin-driven cytotoxicity. Meanwhile, arctigenin increased the levels of p-receptor-interacting serine/threonine-protein kinase 3 (p-RIP3) and p-mixed lineage kinase domain-like pseudokinase (p-MLKL) as necroptosis mediators, and pretreatment with necroptosis inhibitor necrostatin-1 restored their levels and cell viability. Treatment of spheroids with arctigenin resulted in necroptotic cell death, which was prevented by N-acetylcysteine. The siRNA-based knockdown of CCN1 suppressed the levels of MLKL, B-cell lymphoma 2 (Bcl-2), and induced myeloid leukemia cell differentiation (Mcl-1) with increased cleavage of Bcl-2-associated X (Bax) and caspase-3. Collectively, these results provide new insights into the molecular mechanisms underlying arctigenin-induced cytotoxicity, and support arctigenin as a potential therapeutic agent for targeting non-Warburg phenotype through induction of necroptosis via ROS-mediated mitochondrial damage and CCN1 upregulation.
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PMID:Arctigenin induces necroptosis through mitochondrial dysfunction with CCN1 upregulation in prostate cancer cells under lactic acidosis. 3206 51