A novel selenium-containing ruthenium complex Ru(phtpy)(phenSe)Cl(ClO4) (phtpy = 4-phenyl-2,2':6',2''-terpyridine, phenSe = 2-selenicimidazole[4,5-f]1,10-phenanthroline) has been synthesized and found be able to enhance radiation-induced DNA damage through superoxide overproduction, which leads to G2/M arrest and apoptosis in cancer cells by activating ROS-mediated pathways.
Recent evidences show that cationic fluxes play a pivotal role in cell apoptosis. In this study, the roles of Cl− channels in paclitaxel-induced apoptosis were investigated in nasopharyngeal carcinoma CNE-2Z cells. Chloride current and apoptosis were induced by paclitaxel and inhibited by chloride channel blockers. Paclitaxel-activated current possessed similar properties to volume-activated chloride current. After ClC-3 was knocked-down by ClC-3-siRNA, hypotonicity-activated and paclitaxel-induced chloride currents were obviously decreased, indicating that the chloride channel involved in paclitaxel-induced apoptosis may be ClC-3. In early apoptotic cells, ClC-3 was up-regulated significantly; over-expressed ClC-3 was accumulated in cell membrane to form intercrossed filaments, which were co-localized with α-tubulins; changes of ultrastructures and decrease of flexibility in cell membrane were detected by atomic force microscopy. These suggest that ClC-3 is a critical target of paclitaxel and the involvement of ClC-3 in apoptosis may be associated with its accumulation with membrane microtubules and its over activation.
To survive, cells need to avoid excessive volume change that jeopardizes structural integrity and stability of the intracellular milieu. Searching for the molecular identity of volume-regulated anion channel (VRAC) has yielded multiple potential candidates, but none has been confirmed. Recently, it is reported that leucine-rich repeat-containing 8A (LRRC8A) is a main molecular determinant of VRAC current. The biological functions of LRRC8 family proteins are poorly understood, particularly in cancer. In the present study, we investigated LRRC8A in the most common cancers of the digestive system. LRRC8A proteins were found to be abundantly expressed in the esophagus, stomach, duodenum, colon, rectum, liver and pancreas. LRRC8A was elevated in 60% of colorectal cancer patient tissues, which was higher than that in patients with cancer of the esophagus, stomach, duodenum, liver and pancreas. Colon cancer patients with high- expressed LRRC8A had a survival time of 54.9±5.5 months, shorter than that of patients with low-expressed LRRC8A (77.1±3.7). Moreover, survival time (52.6±7.3 months) of patients with metastases in the lymph nodes was shorter than that of patients without positive lymph nodes (72.2±3.6); patients with positive lymph nodes and an elevated LRRC8A expression had the highest mortality rate (~80%). These rates were not observed in rectal cancer. After LRRC8A protein was knocked down in colon cancer HCT116 cells, VRAC currents, migration and tumorigenesis in nude mice were significantly inhibited. In conclusion, we propose that LRRC8A could be a novel prognostic biomarker for colon cancer patient survival, and that the elevated expression of LRRC8A may enhance cancer cell growth and metastasis, and worsen the outcome of patients.
Estrogen plays important roles in regulation of bone formation. Cl channels in the ClC family are expressed in osteoblasts and are associated with bone physiology and pathology, but the relationship between Cl channels and estrogen is not clear. In this study the action of estrogen on Cl channels was investigated in the MC3T3-E1 osteoblast cell line. Our results show that 17β-estradiol could activate a current that reversed at a potential close to the Cl equilibrium potential, with a sequence of anion selectivity of I > Br > Cl > gluconate, and was inhibited by the Cl channel blockers 5-nitro-2-(3-phenylpropylamino)-benzoate and 4,4'-diisothiocyano-2,2'-stilbene disulfonic acid. Knockdown of ClC-3 Cl channel expression by a specific small interfering RNA to ClC-3 attenuated activation of the 17β-estradiol-induced Cl current. Extracellular application of membrane-impermeable 17β-estradiol-albumin conjugates activated a similar current. The estrogen-activated Cl current could be inhibited by the estrogen receptor (ER) antagonist fulvestrant (ICI 182780). The selective ERα agonist, but not ERβ agonist, activated a Cl current similar to that induced by 17β-estradiol. Silencing ERα expression prevented activation of estrogen-induced currents. Immunofluorescence and coimmunoprecipitation experiments demonstrated that ClC-3 Cl channels and ERα were colocalized and closely related in cells. Estrogen promoted translocation of ClC-3 and ERα to the cell membrane from the nucleus. In conclusion, our findings show that Cl channels can be activated by estrogen via ERα on the cell membrane and suggest that the ClC-3 Cl channel may be one of the targets of estrogen in the regulation of osteoblast activity.
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