Epithelial-mesenchymal transition (EMT) is essential for increased invasion and metastasis during cancer progression. Among the candidate EMT-regulating microRNAs that we previously identified, miR-181b-3p was found to induce EMT in MCF7 breast cancer cells, as indicated by an EMT-characteristic morphological change, increased invasiveness, and altered expression of an EMT marker. Transfection with a miR-181b-3p inhibitor reduced the expression of mesenchymal markers and the migration and invasion of highly invasive breast cancer cells. miR-181b-3p induced the upregulation of Snail, a master EMT inducer and transcriptional repressor of E-cadherin, through protein stabilization. YWHAG was identified as a direct target of miR-181b-3p, downregulation of which induced Snail stabilization and EMT phenotypes. Ectopic expression of YWHAG abrogated the effect of miR-181b-3p, including Snail stabilization and the promotion of invasion. In situ hybridization and immunohistochemical analyses indicated that YWHAG expression was inversely correlated with the expression of miR-181b-3p and Snail in human breast cancer tissues. Furthermore, transfection with miR-181b-3p increased the frequency of metastatic nodule formation in the lungs of mice in experimental metastasis assays using MDA-MB-231 cells. Taken together, our data suggest that miR-181b-3p functions as a metastasis activator by promoting Snail-induced EMT, and may therefore be a therapeutic target in metastatic cancers.
Here, we present differential cytotoxic responses to two different doses of photodynamic therapies (PDTs; low-dose PDT [LDP] and high-dose PDT [HDP]) using a chlorin-based photosensitizer, DH-II-24, in human gastric and bladder cancer cells. Fluorescence-activated cell sorting analysis using Annexin V and propidium iodide (PI) showed that LDP induced apoptotic cell death, whereas HDP predominantly caused necrotic cell death. The differential cytotoxic responses to the two PDTs were further confirmed by a DiOC(6) and PI double-staining assay via confocal microscopy. LDP, but not HDP, activated caspase-3, which was inhibited by Z-VAD, Trolox, and BAPTA-AM. LDP and HDP demonstrated opposite effects on intracellular reactive oxygen species (ROS)/Ca(2+) signals; LDP stimulated intracellular ROS production, contributing to a transient increase of intracellular Ca(2+) , whereas HDP induced a massive and prolonged elevation of intracellular Ca(2+) responsible for the transient production of intracellular ROS. In addition, the two PDTs also increased in situ transglutaminase 2 (TG2) activity, with a higher stimulation by HDP, and this increase in activity was prevented by Trolox, BAPTA-AM, and TG2-siRNA. LDP-induced apoptotic cell death was strongly inhibited by Trolox and TG2-siRNA and moderately suppressed by BAPTA-AM. However, HDP-mediated necrotic cell death was partially inhibited by BAPTA-AM but not by TG2-siRNA. Thus, these results demonstrate that LDP and HDP induced apoptotic and necrotic cell death by differential signaling mechanisms involving intracellular Ca(2+) , ROS, and TG2.
Background: The function of transglutaminase 2 (TG2) in dying cells is ambiguous. Results: TG2 activity facilitates simultaneous caspase-dependent and apoptosis-inducing factor-mediated apoptotic cell death via a calpain/Bax signaling pathway. Conclusion: We demonstrated a new mechanism of apoptotic cell death induced by photodynamic therapy (PDT). Significance: Understanding the function of TG2 as a therapeutic target will contribute to improved cancer treatments using PDT.
While photodynamic therapy (PDT) has been recognized as a promising therapeutic modality for the treatment of various cancers and diseases, developments of effective photosensitizers are highly desired to improve the prospect for the use of PDT. In this study, we evaluated DH-II-24, a new photosensitizer, for antitumor PDT in vitro and in vivo. Loaded into human colorectal carcinoma cells (HCT116), DH-II-24 was primarily accumulated in mitochondria, lysosomes, and endoplasmic reticula. Administration of DH-II-24 followed by light exposure induced necrotic cell death in a dose-dependent manner, whereas DH-II-24 in the absence of light induced minimal cell death. In order to investigate the distribution and phamacokinetics of the photosensitizer in vivo, DH-II-24 was intravenously injected to female BALB ⁄ c nude mice. Fluorescence imaging in vivo showed that DH-II-24 was rapidly distributed across the entire body and then mostly eliminated at 24 h. Next, effectiveness of DH-II-24-mediated PDT was examined on colorectal carcinoma xenografts established subcutaneously in BALB ⁄ c nude mice. DH-II-24 (1 mg ⁄ kg, i.v. administration) followed by light exposure significantly suppressed growth of xenograft tumors, compared to light exposure or DH-II-24 alone. Histological examination revealed necrotic damage in PDT-treated tumors, concomitantly with severe damage of tumor vasculature. These results suggest that DH-II-24 is a potential photosensitizer of photodynamic therapy for cancer. (Cancer Sci 2009; 100: 2431-2436) P hotodynamic therapy (PDT) is emerging as a promising non-invasive treatment for cancer.(1-4) PDT involves an administration of a photosensitizer followed by illumination of tumor tissues with visible light of a suitable wavelength for excitation of the photosensitizer. (5,6) The activation of the photosensitizer leads to conversion of molecular oxygen to various highly reactive oxygen species (ROS), which kills tumor cells directly or damages the tumor-associated vasculature.(1,2,7)Tumor vascular damage subsequently deprives the oxygen and nutrients of tumor, resulting in tumor cell death. (2,4,8) In addition, PDT could have a significant stimulatory effect on the immune system. (1,8,9) These multifactorial mechanisms by which PDT mediates tumor destruction have been suggested to be beneficial for long-term tumor control. (7,9) PDT has several advantages over other conventional cancer treatments.(4) Since it requires mere illumination of the tumor site, the treatment is relatively non-invasive.(4) PDT does not induce systemic immunosupression that causes a variety of infections.(8) PDT displays low systemic toxicity and relatively selective destruction of tumors, which is known to be in part due to preferential localization of photosensitizer within tumor.(2,10,11) Thus, PDT has been widely employed to various tumors directly approachable to illumination, such as esophageal carcinoma, head and neck tumors, bladder, prostate, nonmelanoma skin cancers, and actinic keratosis. (7,(12)(13)(14)(15)(16) Compa...
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