RESUMO
The traditional functions of cytoskeletal-associated proteins (CAPs) in line with polymerization and stabilization of the cytoskeleton have evolved and are currently underrated in oncology. Although therapeutic drugs have been developed to target the cytoskeletal components directly in cancer treatment, several recently established therapeutic agents designed for new targets block the proliferation of cancer cells and suppress resistance to existing target agents. It would seem like these targets only work toward inhibiting the polymerization of cytoskeletal components or hindering mitotic spindle formation in cancer cells, but a large body of literature points to CAPs and their culpability in cell signaling, molecular conformation, organelle trafficking, cellular metabolism, and genomic modifications. Here, we review those underappreciated functions of CAPs, and we delineate the implications of cellular signaling instigated by evasive properties induced by aberrant expression of CAPs in response to stress or failure to exert normal functions. We present an analogy establishing CAPs as vulnerable targets for cancer systems and credible oncotargets. This review establishes a paradigm in which the cancer machinery may commandeer the conventional functions of CAPs for survival, drug resistance, and energy generation; an interesting feature overdue for attention.
Assuntos
Proteínas do Citoesqueleto/metabolismo , Progressão da Doença , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Apoptose , Humanos , Microtúbulos/metabolismo , Neoplasias/tratamento farmacológico , Estresse FisiológicoRESUMO
Hypoxia, as an important hallmark of the tumor microenvironment, is a major cause of oxidative stress and plays a central role in various malignant tumors, including glioblastoma. Elevated reactive oxygen species (ROS) in a hypoxic microenvironment promote glioblastoma progression; however, the underlying mechanism has not been clarified. Herein, we found that hypoxia promoted ROS production, and the proliferation, migration, and invasion of glioblastoma cells, while this promotion was restrained by ROS scavengers N-acetyl-L-cysteine (NAC) and diphenyleneiodonium chloride (DPI). Hypoxia-induced ROS activated hypoxia-inducible factor-1α (HIF-1α) signaling, which enhanced cell migration and invasion by epithelial-mesenchymal transition (EMT). Furthermore, the induction of serine protease inhibitor family E member 1 (SERPINE1) was ROS-dependent under hypoxia, and HIF-1α mediated SERPINE1 increase induced by ROS via binding to the SERPINE1 promoter region, thereby facilitating glioblastoma migration and invasion. Taken together, our data revealed that hypoxia-induced ROS reinforce the hypoxic adaptation of glioblastoma by driving the HIF-1α-SERPINE1 signaling pathway, and that targeting ROS may be a promising therapeutic strategy for glioblastoma.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Subunidade alfa do Fator 1 Induzível por Hipóxia , Inibidor 1 de Ativador de Plasminogênio , Humanos , Hipóxia Celular , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glioblastoma/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Microambiente Tumoral , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologiaRESUMO
AIMS: Glioblastoma is the central nervous system tumor with the highest mortality rate, and the clinical effectiveness of chemotherapy is low. Curzerene can inhibit the progression of non-small-cell lung cancer, but its role in glioma has not been reported. The purpose of this study was to clarify the effect of curzerene on glioma progression and further explore its potential mechanism. METHODS: The expression of glutathione S-transferase A4 (GSTA4) in glioblastoma and the effect of curzerene on the expression of GSTA4 and matrix metalloproteinase 9 and the activation of the mTOR pathway were detected by Western blotting and RT-PCR, and the effects of curzerene treatment on glioma malignant character were detected by cell biological assays. The in vivo antitumor effects of curzerene were analyzed in a nude mouse xenograft model. RESULTS: Curzerene was found to inhibit the expression of GSTA4 mRNA and protein in U251 and U87 glioma cells, and this effect correlated with a downregulation of the proliferation of these cells in a time- and dose-dependent manner. Invasion and migration were also inhibited, and curzerene treatment correlated with induction of apoptosis. Curzerene inhibited the activation of the mTOR pathway and the expression of matrix metalloproteinase 9, and it correlated with increased 4-hydroxynonenal levels. In vivo, curzerene was found to significantly inhibit tumor growth in nude mice and to prolong the survival time of tumor-bearing nude mice. CONCLUSION: In conclusion, inhibition of GSTA4 correlates with positive outcomes in glioma models, and thus, this molecule is a candidate drug for the treatment of glioma.
Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Glioblastoma , Neoplasias Pulmonares , Animais , Apoptose , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Glioblastoma/metabolismo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Glutationa Transferase/farmacologia , Humanos , Camundongos , Camundongos Nus , Sesquiterpenos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Herein, we design a room-temperature spin-valve-like magnetoresistance in a nano-column Fe3O4/Ni heterostructure without using a non-magnetic spacer or pinning layer. An Fe3O4 nano-column film is self-assembled on a Ni underlayer by the thermal decomposition method. The wet-chemical self-assembly is facile, economical and scalable. The magnetoresistance (MR) response of the Ni underlayer in the heterostructure under positive and negative out-of-plane magnetic fields differ by â¼0.25 at room temperature and â¼0.43 at 100 K. We attribute the spin-valve-like magnetoresistance to the unidirectional magnetic anisotropy of the Ni underlayer when being magnetically coupled by the Fe3O4 nano-column film. The out-of-plane negative-field magnetization is higher than the positive-field magnetization, affirming the unidirectional magnetic anisotropy of the Fe3O4/Ni heterostructure. Temperature-dependent magnetic and resistivity studies illustrate a close correlation between the magnetization transition of Fe3O4 and resistivity transition of Ni and prove a magnetic coupling between the Fe3O4 and Ni. First-principles calculations reveal that the Fe3O4/Ni model under a negative magnetic field is energetically more stable than that under a positive magnetic field. Furthermore, partial density of states (PDOS) analysis demonstrates the unidirectional magnetic anisotropy of the Ni 3d orbital. This is induced by the strong ferromagnetic coupling between Fe3O4 and Ni via oxygen-mediated Fe 3d-O 2p-Ni 3d hybridizations.