New insights into pharmacological tools to TR(i)P cancer up.

The aim of this review is to address the recent advances regarding the use of pharmacological agents to target transient receptor potential (TRP) channels in cancer and their potential application in therapeutics. Physiologically, TRP channels are responsible for cation entry (Ca(2+) , Na(+) , Mg(2+) ) in many mammalian cells and regulate a large number of cellular functions. However, dysfunction in channel expression and/or activity can be linked to human diseases like cancer. Indeed, there is growing evidence that TRP channel expression is altered in cancer tissues in comparison with normal ones. Moreover, these proteins are involved in many cancerous processes, including cell proliferation, apoptosis, migration and invasion, as well as resistance to chemotherapy. Among the TRP superfamily, TRPC, TRPV, TRPM and TRPA1 have been shown to play a role in many cancer types, including breast, digestive, gliomal, head and neck, lung and prostate cancers. Pharmacological modulators are used to characterize the functional implications of TRP channels in whole-cell membrane currents, resting membrane potential regulation and intracellular Ca(2+) signalling. Moreover, pharmacological modulation of TRP activity in cancer cells is systematically linked to the effect on cancerous processes (proliferation, survival, migration, invasion, sensitivity to chemotherapeutic drugs). Here we describe the effects of such TRP modulators on TRP activity and cancer cell phenotype. Furthermore, the potency and specificity of these agents will be discussed, as well as the development of new strategies for targeting TRP channels in cancer.

Transient receptor potential melastatin 7 is involved in oestrogen receptor-negative metastatic breast cancer cells migration through its kinase domain.

Oestrogen receptor negative (ER(-)) invasive ductal carcinoma (IDC) represents a significant clinical challenge and therefore prompts the discovery of novel biomarkers. Transient receptor potential melastatin 7 (TRPM7), a channel protein that also contains a regulatory kinase domain, is overexpressed in IDC and regulates migration. However, the molecular mechanism remains poorly defined. Here, we examined whether TRPM7 regulates migration by its channel function or by its kinase domain. A Magnesium Inhibited Cation current was recorded in two ER(-) highly metastatic breast cancer cell lines. Down-regulation of TRPM7 neither affected Ca(2+)-, nor Mg(2+)-homoeostasis but significantly reduced cell migration via a Ca(2+)-independent pathway. Notably, the overexpression of the truncated kinase domain form of TRPM7 decreased cell migration, while the overexpression of the wild-type form strongly increased it. Concomitantly, TRPM7 silencing reduced the myosin IIA heavy chain phosphorylation. Furthermore, we found higher TRPM7 expression in ER(-) IDC tissues and lymph nodes than in the non-invasive tumoural samples. In conclusion, TRPM7 plays a critical role in breast cancer cell migration through its kinase domain, and our data support the consideration of using TRPM7 as a novel biomarker and a potential therapeutic target in the treatment of human ER(-) IDC.

Explaining and predicting differences in meat quality through stress reactions at slaughter: The case of Large White and Duroc pigs.

Large White and Duroc pigs (n=42) were group-reared on straw. Durocs were more active in the home pens and had higher basal urinary cortisol levels. During tests, Durocs touched more often an unfamiliar human, but not an unfamiliar object, than Large Whites. Pigs were experimentally (low stress) or industrially (high stress) slaughtered. Meat (Longissimus lumborum (LL), Biceps femoris (BF), Adductor femoris (AF) and Semimembranosus (SM)) was darker, more yellow, had higher ultimate pH and better water holding capacity after high, compared to low-stress slaughter. Large White meat contained less pre-slaughter glycogen, was redder and lost more drip. Slaughter conditions influenced ultimate pH of Large White more than of Duroc meat. Large Whites, and to a lesser extent Durocs, touching the human less often during the test, had faster early post-mortem LL and BF muscle metabolism. Pigs exploring the unfamiliar object more often were more aggressive during pre-slaughter mixing and had higher AF and SM ultimate pH.