Abstract
TW-37 is a small-molecule inhibitor of Bcl-2 family proteins, which can induce anti-cancer activities in various types of cancer. In the current study, we investigated the potential molecular mechanism underlying the differential response to TW-37-induced apoptosis in two human mucoepidermoid carcinoma (MEC) cell lines. The differential response and underlying molecular mechanism of human MEC cells to TW-37 was evaluated by trypan blue exclusion assay, western blotting, 4’, 6-diamidino-2-phenylindole staining, annexin V/propidium iodide double staining, analysis of the sub-G1 population, human apoptosis array, and measurements of intracellular reactive oxygen species (ROS). TW-37 decreased cell viability and induced apoptosis in YD-15 cells, but not in MC3 cells. Proteome profiling using a human apoptosis array revealed four candidate proteins and of these, heme oxygenase-1 (HO-1) was mainly related to the differential response to TW-37 of YD-15 and MC3 cells. TW-37 also led to a significant increase in intracellular levels of ROS in YD-15 cells, which is associated with apoptosis induction. The ectopic expression of HO-1 recovered YD-15 cells from TW-37-induced apoptosis by reducing intracellular levels of ROS. The expression of HO-1 was reduced through both transcriptional and post-translational modification during TW-37-mediated apoptosis. We conclude that HO-1 is a potential indicator to estimate response to TW37-induced apoptosis in human MEC.
Highlights
Salivary gland tumors account for about 0.5% of all malignancies and less than 5% of all head and neck cancers [1]
To investigate the anti-proliferative effects of TW-37 in two human Mucoepidermoid carcinoma (MEC) cell lines (MC3 and YD-15) in vitro, both cell lines were treated with vehicle control (DMSO) or 1.25 μM TW-37 for the indicated time points
To determine whether the anti-proliferative effects of TW-37 were related to the induction of an apoptotic response, we examined levels of poly (ADP-ribose) polymerase (PARP) cleavage, a hallmark of apoptosis
Summary
Salivary gland tumors account for about 0.5% of all malignancies and less than 5% of all head and neck cancers [1]. Mucoepidermoid carcinoma (MEC) is the most common malignant cancer in salivary glands, but there are no effective strategies to manage MEC because of its rarity. Several published studies have demonstrated the anti-tumor activities of single or combination chemotherapy with cisplatin, paclitaxel, or cetuximab [1,2]. We recently observed that MECs are effective in chemotherapy through a variety of molecular mechanisms in vitro [3,4]. Current approaches to treating MEC remain disappointing.
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