Maximizing spin-orbit torque efficiency of Ta(O)/Py via modulating oxygen-induced interface orbital hybridization

Spin-orbit torques due to interfacial Rashba and spin Hall effects have been widely considered as a potentially more efficient approach than the conventional spin-transfer torque to control the magnetization of ferromagnets. We report a comprehensive study of spin-orbit torque efficiency in Ta(O)/Ni81Fe19 bilayers by tuning low-oxidation of \b{eta}-phase tantalum, and find that the spin Hall angle {\theta}DL increases from ~ -0.18 of the pure Ta/Py to the maximum value ~ -0.30 of Ta(O)/Py with 7.8% oxidation. Furthermore, we distinguish the efficiency of the spin-orbit torque generated by the bulk spin Hall effect and by interfacial Rashba effect, respectively, via a series of Py/Cu(0-2 nm)/Ta(O) control experiments. The latter has more than twofold enhancement, and even more significant than that of the former at the optimum oxidation level. Our results indicate that 65% enhancement of the efficiency should be related to the modulation of the interfacial Rashba-like spin-orbit torque due to oxygen-induced orbital hybridization cross the interface. Our results suggest that the modulation of interfacial coupling via oxygen-induced orbital hybridization can be an alternative method to boost the change-spin conversion rate.Comment: 15 pages, 4 figure

δ-Tocotrienol Induces Human Bladder Cancer Cell Growth Arrest, Apoptosis and Chemosensitization through Inhibition of STAT3 Pathway

<div><p>Vitamin E intake has been implicated in reduction of bladder cancer risk. However, the mechanisms remain elusive. Here we reported that δ-tocotrienol (δ-T3), one of vitamin E isomers, possessed the most potent cytotoxic capacity against human bladder cancer cells, compared with other Vitamin E isomers. δ-T3 inhibited cancer cell proliferation and colonogenicity through induction of G1 phase arrest and apoptosis. Western blotting assay revealed that δ-T3 increased the expression levels of cell cycle inhibitors (p21, p27), pro-apoptotic protein (Bax) and suppressed expression levels of cell cycle protein (Cyclin D1), anti-apoptotic proteins (Bcl-2, Bcl-x_L and Mcl-1), resulting in the Caspase-3 activation and cleavage of PARP. Moreover, the δ-T3 treatment inhibited ETK phosphorylation level and induced SHP-1 expression, which was correlated with downregulation of STAT3 activation. In line with this, δ-T3 reduced the STAT3 protein level in nuclear fraction, as well as its transcription activity. Knockdown of SHP-1 partially reversed δ-T3-induced cell growth arrest. Importantly, low dose of δ-T3 sensitized Gemcitabine-induced cytotoxic effects on human bladder cancer cells. Overall, our findings demonstrated, for the first time, the cytotoxic effects of δ-T3 on bladder cancer cells and suggest that δ-T3 might be a promising chemosensitization reagent for Gemcitabine in bladder cancer treatment.</p></div

δ-T3 induced cell cycle arrest in T24 (A, B) and 5637 cells (C, D) bladder cancer cells.

<p>Cells were treated by δ-T3 ranging from 0–150 μM for 48 h. Cell cycle distribution and Sub-G1 ratios were assessed by flow cytometry. *, <i>P</i> < 0.05; **, <i>P</i> < 0.01; ***, <i>P</i> < 0.001.</p

δ-T3 induces apoptosis in bladder cancer cells.

<p>Annexin V/PI analysis showed that δT3 induced apoptosis in T24 (A) and 5637 (B) bladder cancer cells, as compared to vehicle treated control cells.</p

Low concentration of δ-T3 enhanced the anti-cancer effects of Gemcitabine (GEM) on bladder cancer cell growth.

<p>(A) T24 and 5637 cells were incubated for 48 h in the presence of 25 μM δ-T3 and/or 0.08 μM GEM. Then, the percentage of cell viability was determined by MTT assay. (B) T24 and 5637 cells were cultured for 48 h in the absence or presence of 25 μM δ-T3 and/or 0.08 μM GEM, respectively. Apoptotic rates were analyzed by Annexin V/PI staining assay. (C) Combined treatment with GEM (0.08 μM) and δ-T3 (25 μM) for 14 days completely eliminated the colony formation capacity of T24 cells. (D) Western blotting analysis of the apoptosis-related and STAT3 signaling-related protein levels in T24 cells, treated with δ-T3 and/or GEM for 48 h. (E) Western blotting analysis of the STAT3 signaling-related protein levels in T24 cells, treated with δ-T3 and/or GEM for 24h. **, <i>P</i> < 0.01; ***, <i>P</i> < 0.001.</p

δ-T3 suppresses STAT3 signaling pathways in human bladder cancer cells.

<p>Western blotting analysis of the STAT3/ETK signaling pathway-related (A) and SHP-1 (B) protein levels in T24 and 5637 cells under the δ-T3 treatment for 24 h. Western bands were quantified by Image J software and the digits shown below the upper panel were the relative STAT3 expression levels normalized by loading controls. (C) Reduction of nuclear STAT3 protein level upon the treatment of 150 μM δ-T3 in T24 cells. LaminB1 was used as a nuclear loading control. Tubulin was used as a cytoplasmic loading control. (D) Genomic structure of <i>bclxl</i> gene was shown, with the labels of three primer sets for ChIP assay. Primer set 1 and 2 contain STAT3 binding element; whereas primer set 3 (NC) serves as negative control. STAT3 occupancy in the <i>bclxl</i> promoter in bladder cancer cell line T24 treated with 150 μM δ-T3 or vehicle for 18 h were assayed by ChIP assay. Input DNA and immunoprecipitated DNA were analyzed by qPCR analyses using primer sets depicted above and normalized by IgG control. The error bar indicates the means ± SD. ***, <i>P <</i> 0.001. (E) δ-T3 treatment reduced the STAT3 downstream target genes (<i>bcl2</i>, <i>bclxl</i> and <i>mcl-1</i>) expression at mRNA level. (F) Luciferase activity analysis of STAT3-Luc upon the treatment of 150 μM δ-T3 in T24 cells for 24 h. TK-Renilla luciferase plasmid was used as internal control. (G) Knockdown efficiency of SHP-1 in T24 cells by Western blotting assay. β–Actin was used as internal control. siNC, negative control siRNA. siSHP-1, siRNA targeting to SHP-1. (H) T24 cells were treated with siRNA to SHP-1 or siNC, followed by treatment with δ-T3 or vehicle. Cell viability was tested by MTT assay. **, <i>P</i> < 0.01; ***, <i>P</i> < 0.001.</p

Steroid Receptor Coactivator-3 Regulates Glucose Metabolism in Bladder Cancer Cells through Coactivation of Hypoxia Inducible Factor 1α

Cancer cell proliferation is a metabolically demanding process, requiring high glycolysis, which is known as Warburg effect, to support anabolic growth. Steroid receptor coactivator-3 (SRC-3), a steroid receptor coactivator, is overexpressed and/or amplified in multiple cancer types, including non-steroid targeted cancers, such as urinary bladder cancer (UBC). However, whether SRC-3 regulates the metabolic reprogramming for cancer cell growth is unknown. Here, we reported that overexpression of SRC-3 accelerated UBC cell growth, accompanied by the increased expression of genes involved in glycolysis. Knockdown of SRC-3 reduced the UBC cell glycolytic rate under hypoxia, decreased tumor growth in nude mice, with reduction of proliferating cell nuclear antigen and lactate dehydrogenase expression levels. We further revealed that SRC-3 could interact with hypoxia inducible factor 1α (HIF1α), which is a key transcription factor required for glycolysis, and coactivate its transcriptional activity. SRC-3 was recruited to the promoters of HIF1α-target genes, such as glut1 and pgk1. The positive correlation of expression levels between SRC-3 and Glut1 proteins was demonstrated in human UBC patient samples. Inhibition of glycolysis through targeting HK2 or LDHA decelerated SRC-3 overexpression-induced cell growth. In summary, overexpression of SRC-3 promoted glycolysis in bladder cancer cells through HIF1α to facilitate tumorigenesis, which may be an intriguing drug target for bladder cancer therapy