Emmanuelle Germain

Significance: Transient receptor potential vanilloid subfamily member 6 (TRPV6) is a highly selective Ca ²⁺ channel that exercises its normal physiological function via Ca ²⁺ absorption in the intestine and kidney. Intriguingly, we show that the TRPV6 channel may switch from its well-known constitutive activity to the store operated due to the remodeling mechanism involving STIM1/Orai1/TRPC1-induced activation of TRPV6 channel translocation to the plasma membrane via the Ca ²⁺ /Annexin I/S100A11 pathway. Moreover, we demonstrate that the discovered mechanism is used by prostate cancer cells. This channel is absent in healthy prostate and is expressed de novo in prostate cancer cells, where it changes the role by supplying Ca ²⁺ , which is used in cancer to increase cell survival.

Purpose: Given that nerve growth factor has previously been shown to be involved in breast cancer progression, we have tested here the hypothesis that the other neurotrophins (NT) are expressed and have an influence in breast tumor growth.

Background: Although several anti-angiogenic therapies have been approved in the treatment of cancer, the survival benefits of such therapies are relatively modest. Discovering new molecules and/or better understating signaling pathways of angiogenesis is therefore essential for therapeutic improvements. The objective of the present study was to determine the involvement of nerve growth factor (NGF) in breast cancer angiogenesis and the underlying molecular mechanisms. Results: We showed that both recombinant NGF and NGF produced by breast cancer cells stimulated angiogenesis in Matrigel plugs in immunodeficient mice. NGF strongly increased invasion, cord formation and the monolayer permeability of endothelial cells. Moreover, NGF-stimulated invasion was under the control of its tyrosine kinase receptor (TrkA) and downstream signaling pathways such as PI3K and ERK, leading to the activation of matrix metalloprotease 2 and nitric oxide synthase. Interestingly, NGF increased the secretion of VEGF in both endothelial and breast cancer cells. Inhibition of VEGF, with a neutralizing antibody, reduced about half of NGF-induced endothelial cell invasion and angiogenesis in vivo. Conclusions: Our findings provided direct evidence that NGF could be an important stimulator for breast cancer angiogenesis. Thus, NGF, as well as the activated signaling pathways, should be regarded as potential new targets for anti-angiogenic therapy against breast cancer.

The metabolism of dipropyl disulphide (DPDS), a sulphur compound from onion, was investigated in vivo in the rat. A single dose (200 mg kg⁻¹) was administered by gastric intubation and the time courses of DPDS and its metabolites were followed over 48 h by gas chromatography coupled with mass spectrometry in the stomach, intestine, liver, and blood. DPDS was detected in the stomach where it was transformed into propyl mercaptan, whereas the liver contained only traces of DPDS and none at all in the other examined organs. The metabolites methylpropyl sulphide, methylpropyl sulphoxide (MPSO), and methylpropyl sulphone (MPSO₂) were sequentially formed in the liver. The route of elimination from the liver seemed to be mainly via the blood. The bile also participated in the excretory process, but only for MPSO₂. The pharmacokinetic parameters were determined for all of the above compounds. Whereas the bioavailability of DPDS was very low (0.008 h mM), the areas under the curve were higher for the S-oxidized metabolites MPSO and MPSO₂, i.e. 9.64 and 24.15 h mM, respectively. The half-lives for DPDS and its metabolites varied between 2.0 and 8.25 h, except for MPSO₂, which had a half-life of 29.6 h. MPSO₂ was the most abundant and persistent of these metabolites.

Polyunsaturated fatty acids (PUFAs) have been reported to enhance the efficacy of chemotherapeutic agents that produce reactive oxygen species such as anthracyclines. We previously reported in a human breast cancer cell line that the increased cytotoxic activity of anthracyclines by several PUFAs was abolished by antioxidants and enhanced by pro-oxidants, suggesting that lipid peroxidation was involved in this effect. To determine the relevance of this observation in vivo, we examined the effect of the oxidative status of the diet on the activity of epirubicin against N-methylnitrosourea–induced mammary tumors in Sprague-Dawley rats. Three groups of rats were fed a basal diet enriched with dietary n-3 PUFA (sardine oil, 15%) alone (control group), with addition of an antioxidant (α-tocopherol, 100 UI/kg diet), or with addition of an oxidant system (dehydroascorbate/naphthoquinone). When the first mammary tumor reached 1 cm2, epirubicin was administrated weekly for 3 wk, and subsequent change in ...

Chromatin is a dynamic macromolecular structure epigenetically modified to regulate specific gene expression. Altered chromatin function can lead to aberrant expression of growth regulators and may, ultimately, cause cancer. That many human diseases have epigenetic etiology has stimulated the development of 'epigenetic' therapies. Inhibitors of histone deacetylases (HDACIs) induce proliferation arrest, maturation and apoptosis of cancer cells, but not normal cells, in vitro and in vivo, and are currently being tested in clinical trials^1,2,3,4,5. We investigated the mechanism(s) underlying this tumor selectivity. We report that HDACIs induce, in addition to p21, expression of TRAIL (Apo2L, TNFSF10) by directly activating the TNFSF10 promoter, thereby triggering tumor-selective death signaling in acute myeloid leukemia (AML) cells and the blasts of individuals with AML. RNA interference revealed that the induction of p21, TRAIL and differentiation are separable activities of HDACIs. HDACIs induced proliferation arrest, TRAIL-mediated apoptosis and suppression of AML blast clonogenicity irrespective of French-American-British (FAB) classification status, karyotype and immunophenotype. No apoptosis was seen in normal CD34⁺ progenitor cells. Our results identify TRAIL as a mediator of the anticancer action of HDACIs.