Ferroptosis, a form of regulated cell death caused by lipid peroxidation, was recently identified as a natural tumor suppression mechanism. Here, we show that ionizing radiation (IR) induces ferroptosis in cancer cells. Mechanistically, IR induces not only reactive oxygen species (ROS) but also the expression of ACSL4, a lipid metabolism enzyme required for ferroptosis, resulting in elevated lipid peroxidation and ferroptosis. ACSL4 ablation largely abolishes IR-induced ferroptosis and promotes radioresistance. IR also induces the expression of ferroptosis inhibitors, including SLC7A11 and GPX4, as an adaptive response. IR-or KEAP1 deficiencyinduced SLC7A11 expression promotes radioresistance through inhibiting ferroptosis. Inactivating SLC7A11 or GPX4 with ferroptosis inducers (FINs) sensitizes radioresistant cancer cells and xenograft tumors to IR. Furthermore, radiotherapy induces ferroptosis in cancer patients, and increased ferroptosis correlates with better response and longer survival to radiotherapy in cancer patients. Our study reveals a previously unrecognized link between IR and ferroptosis and indicates that further exploration of the combination of radiotherapy and FINs in cancer treatment is warranted.

Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is highly inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient availability remains unclear. In this study, we perform integrated proteomic and functional analyses to reveal that SLC7A11-mediated cystine uptake promotes not only GSH synthesis, but also GPX4 protein synthesis. Mechanistically, we find that cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the Rag-mTORC1-4EBP signaling axis. We show that pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest using combinatorial therapy of mTORC1 inhibitors and ferroptosis inducers in cancer treatment.

The surface chemistry of materials has an interactive influence on cell behavior. The optimal adhesion of mammalian cells is critical in determining the cell viability and proliferation on substrate surfaces. Because of the inherent high hydrophobicity of a poly(dimethylsiloxane) (PDMS) surface, cell culture on these surfaces is unfavorable, causing cells to eventually dislodge from the surface. Although physically adsorbed matrix proteins can promote initial cell adhesion, this effect is usually short-lived. Here, (3-aminopropyl)triethoxy silane (APTES) and cross-linker glutaraldehyde (GA) chemistry was employed to immobilize either fibronectin (FN) or collagen type 1 (C1) on PDMS. The efficiency of these surfaces to support the adhesion and viability of mesenchymal stem cells (MSCs) was analyzed. The hydrophobicity of the native PDMS decreased significantly with the mentioned surface functionalization. The adhesion of MSCs was mostly favorable on chemically modified PDMS surfaces with APTES + GA + protein. Additionally, the spreading area of MSCs was significantly higher on APTES + GA + C1 surfaces than on other unmodified/modified PDMS surfaces with C1 adsorption. However, there were no significant differences in the MSC spreading area on the unmodified/modified PDMS surfaces with FN adsorption. Furthermore, there was a significant increase in cell proliferation on the PDMS surface with APTES + GA + protein functionalization as compared to the PDMS surface with protein adsorption only. Therefore, the covalent surface chemical modification of PDMS with APTES + GA + protein could offer a more biocompatible platform for the enhanced adhesion and proliferation of MSCs. Similar strategies can be applied for other substrates and cell lines by appropriate combinations of self-assembly monolayers (SAMs) and extracellular matrix proteins.

SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here, we show that this comes at a significant cost for cancer cells with high SLC7A11 expression. Actively importing cystine is potentially toxic due to its low solubility, forcing SLC7A11-high cancer cells to constitutively reduce cystine to the more soluble cysteine. This presents a substantial drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway (PPP). Limiting glucose supply to SLC7A11-high cancer cells results in marked accumulation of intracellular cystine, redox system collapse, and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that glucose transporter (GLUT) inhibitors selectively kill SLC7A11-high cancer cells and suppress SLC7A11-high tumor growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the PPP, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11-high cancers.

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Abstract-Cloud computing is becoming popular. Building high-quality cloud applications is a critical research problem. QoS rankings provide valuable information for making optimal cloud service selection from a set of functionally equivalent service candidates. To obtain QoS values, real-world invocations on the service candidates are usually required. To avoid the time-consuming and expensive real-world service invocations, this paper proposes a QoS ranking prediction framework for cloud services by taking advantage of the past service usage experiences of other consumers. Our proposed framework requires no additional invocations of cloud services when making QoS ranking prediction. Two personalized QoS ranking prediction approaches are proposed to predict the QoS rankings directly. Comprehensive experiments are conducted employing real-world QoS data, including 300 distributed users and 500 realworld web services all over the world. The experimental results show that our approaches outperform other competing approaches.

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