Ferroptosis is an intracellular iron-dependent form of cell death that is distinct from apoptosis, necrosis, and autophagy. Extensive studies suggest that ferroptosis plays a pivotal role in tumor suppression, thus providing new opportunities for cancer therapy. The development of resistance to cancer therapy remains a major challenge. A number of preclinical and clinical studies have focused on overcoming drug resistance. Intriguingly, ferroptosis has been correlated with cancer therapy resistance, and inducing ferroptosis has been demonstrated to reverse drug resistance. Herein, we provide a detailed description of the mechanisms of ferroptosis and the therapeutic role of regulating ferroptosis in reversing the resistance of cancer to common therapies, such as chemotherapy, targeted therapy and immunotherapy. We discuss the prospect and challenge of regulating ferroptosis as a therapeutic strategy for reversing cancer therapy resistance and expect that our review could provide some references for further studies.

Tumor necrosis factor (TNF) plays an important role in the pathogenesis of inflammatory bone loss through stimulation of osteoclastic bone resorption and inhibition of osteoblastic bone formation. Compared with the well established role of TNF in osteoclastogenesis, mechanisms by which TNF inhibits osteoblast function have not been fully determined. Runx2 is an osteoblast-specific transcription factor whose steady-state protein levels are regulated by proteasomal degradation, mediated by the E3 ubiquitin ligases, Smurf1 and Smurf2. We hypothesized that TNF inhibits osteoblast function through Smurf-mediated Runx2 degradation. We treated C2C12 and 2T3 osteoblast precursor cell lines and primary osteoblasts with TNF and found that TNF, but not interleukin-1, significantly increased Smurf1 and Smurf2 expression. TNF increased the degradation of endogenous or transfected Runx2 protein, which was blocked by treating cells with a proteasomal inhibitor or by infecting cells with small interfering (si)RNA against Smurf1 or Smurf2. TNF inhibited the expression of bone morphogenetic protein and transforming growth factor-␤ signaling reporter constructs, and the inhibition of each was blocked by Smurf1 siRNA and Smurf2 siRNA, respectively. Overexpression of Smurf1 and/or Smurf2 siRNAs prevented the inhibitory effect of TNF on Runx2 reporter. Consistent with these in vitro findings, bones from TNF transgenic mice or TNF-injected wild type mice had increased Smurf1 and decreased Runx2 protein levels. We propose that one of the mechanisms by which TNF inhibits bone formation in inflammatory bone disorders is by promoting Runx2 proteasomal degradation through up-regulation of Smurf1 and Smurf2 expression. Tumor necrosis factor (TNF)2 is a major contributor to pathologic bone loss through stimulation of osteoclastic bone resorption and inhibition of osteoblastic bone formation. In patients with rheumatoid arthritis, TNF and other cytokines are overproduced in inflamed joints by various cells infiltrating the synovial membrane. This leads to severe local erosion of cartilage and bone, periarticular osteopenia, as well as systemic osteoporosis (1, 2). Under these conditions, osteoblasts do not catch up with the accelerated bone resorption, indicating impaired osteoblast function (3). The inhibitory effects of TNF on bone formation in vitro were first described in 1987 in neonatal rat calvarial organ cultures (4). Subsequent studies demonstrated that TNF inhibits recruitment of osteoblast progenitors, reduces expression of genes produced by mature osteoblasts, and promotes osteoblast apoptosis through nuclear factor-B signaling pathway (5-9). However, compared with our understanding of the role of TNF in osteoclast biology, little is known of the molecular mechanisms that mediate the effect of TNF on osteoblast inhibition.To date, the most important mechanistic finding of TNF-mediated osteoblast inhibition was the demonstration that TNF decreases Runtrelated gene 2 (Runx2) expression and its DNA binding activity in osteoblasts (10...

Objective. This study was undertaken to investigate the effect of lymphatic inhibition on joint and draining lymph node (LN) pathology during the course of arthritis progression in mice.Methods. Tumor necrosis factor (TNF)-transgenic mice were used as a model of chronic inflammatory arthritis. Mice were subjected to contrastenhanced magnetic resonance imaging to obtain ankle and knee joint synovial volumes and draining popliteal LN volumes before and after 8 weeks of treatment with vascular endothelial growth factor receptor 3 (VEGFR-3) neutralizing antibody, VEGFR-2 neutralizing antibody, or isotype IgG. Animals were subjected to near-infrared lymphatic imaging to determine the effect of VEGFR-3 neutralization on lymph transport from paws to draining popliteal LNs. Histologic, immunohistochemical, and reverse transcriptase-polymerase chain reaction analyses were used to examine lymphatic vessel formation and the morphology of joints and popliteal LNs.Results. Compared with IgG treatment, VEGFR-3 neutralizing antibody treatment significantly decreased the size of popliteal LNs, the number of lymphatic vessels in joints and popliteal LNs, lymphatic drainage from paws to popliteal LNs, and the number of VEGF-C-expressing CD11b؉ myeloid cells in popliteal LNs. However, it increased the synovial volume and area of inflammation in ankle and knee joints. VEGFR-2 neutralizing antibody, in contrast, inhibited both lymphangiogenesis and joint inflammation.Conclusion. These findings indicate that lymphangiogenesis and lymphatic drainage are reciprocally related to the severity of joint lesions during the development of chronic arthritis. Lymphatic drainage plays a beneficial role in controlling the progression of chronic inflammation.Lymphatic vessels are present in almost all tissues of the body. They are composed of an extensive network of thin-walled capillaries that drain protein-rich lymph from extracellular spaces (1). Under normal conditions, the major functions of the lymphatic system include maintenance of tissue fluid homeostasis, absorption of fatty acids, and mediation of the afferent immune response (2,3). Recent studies have provided increasing evidence that the lymphatic system also plays key roles in disease processes such as cancer metastasis, lymphedema, obesity, and inflammation (4,5).

Angiogenesis is involved in the pathogenesis of inflammatory arthritis, but little is known about the role of lymphangiogenesis in this setting. Here, we examined whether tumor necrosis factor (TNF) stimulates osteoclast precursors (OCPs) to produce the lymphatic growth factor, vascular endothelial growth factor-C (VEGF-C), and induce lymphangiogenesis. We used TNF-transgenic (Tg) mice and mice with serum-induced arthritis. OCPs were purified by fluorescence-activated cell sorting of CD11b + /Gr-1 -/lo blood or bone marrow cells and subjected to microarray analysis or were generated from spleen or joint cells and treated with TNF. Expression of VEGFs was analyzed and examined by real-time reverse transcription-polymerase chain reaction and Western blotting. Immunostaining and magnetic resonance imaging were used to quantify lymphatic vessels and volumes of synovium and draining lymph nodes. TNF stimulated VEGF-C expression by OCPs and increased nuclear factor-kappa B (NF-κB) binding to an NF-κB sequence in the VEGF-C promoter. OCPs from joints of TNF-Tg mice express high levels of VEGF-C. Lymphatic vessel numbers and size were markedly increased in joint sections of TNF-Tg mice and mice with serum-induced arthritis. The severity of synovitis correlated with draining lymph node size. In summary, TNF induces OCPs to produce VEGF-C through NF-κB, leading to significantly increased lymphangiogenesis in joints of arthritic mice. The lymphatic system may play an important role in the pathogenesis of inflammatory arthritis.