Protein tyrosine kinase (PTK) is one of the major signaling enzymes in the process of cell signal transduction, which catalyzes the transfer of ATP-γ-phosphate to the tyrosine residues of the substrate protein, making it phosphorylation, regulating cell growth, differentiation, death and a series of physiological and biochemical processes. Abnormal expression of PTK usually leads to cell proliferation disorders, and is closely related to tumor invasion, metastasis and tumor angiogenesis. At present, a variety of PTKs have been used as targets in the screening of anti-tumor drugs. Tyrosine kinase inhibitors (TKIs) compete with ATP for the ATP binding site of PTK and reduce tyrosine kinase phosphorylation, thereby inhibiting cancer cell proliferation. TKI has made great progress in the treatment of cancer, but the attendant acquired acquired resistance is still inevitable, restricting the treatment of cancer. In this paper, we summarize the role of PTK in cancer, TKI treatment of tumor pathways and TKI acquired resistance mechanisms, which provide some reference for further research on TKI treatment of tumors.

Ubiquitin E3 ligase CUL4A plays important oncogenic roles in the development of cancers. DTL, one of the CUL4-DDB1 associated factors (DCAFs), may involve in the process of cancer development. Programmed cell death 4 (PDCD4) is a tumor suppressor gene involved in cell apoptosis, transformation, invasion and tumor progression. Affinity-purification mass spectrometry was used to identify potential DTL interaction proteins. Co-immunoprecipitation (Co-IP) was performed to verify protein interaction between DTL and PDCD4. mRNA levels in cancer cells and tissues were detected by Quantitative real-time PCR. Lentivirus was used to establish stable overexpression and knocking down cell lines for DTL and PDCD4. Transwell and wound healing assays were used to determine migration ability of cancer cells. Matrigel assay was used to determine invasion ability of cancer cells. MTT and colony formation assays were used to evaluate proliferation of cancer cells. In this study, programmed cell death 4 (PDCD4) was identified as a potential substrate of DTL. Co-IP and immunofluorescence assays further confirmed the interaction between DTL and PDCD4. Moreover, DTL overexpression decreased the protein level and accelerated the degradation rate of PDCD4. Through in vitro ubiquitination experiment, we proved that PDCD4 was degraded by DTL through ubiquitination. Clinically DTL was significantly up-regulated in cancer tissues than that in normal tissues. The survival curves showed that cancer patients with higher DTL expression owned lower survival rate. Functional experiments showed that DTL not only enhanced the proliferation and migration abilities of cancer cells, but also promoted the tumorigenesis in nude mice. Rescued experiment results demonstrated that silencing PDCD4 simultaneous with DTL recovered the phenotypes defect caused by DTL knocking down. Our results elucidated that DTL enhanced the motility and proliferation of cancer cells through degrading PDCD4 to promote the development of cancers.

Hypoxia is a common phenomenon in most malignant tumors, especially in pancreatic cancer (PC). Hypoxia is the result of unlimited tumor growth and plays an active role in promoting tumor survival, progression, and invasion. As the part of the hypoxia microenvironment in PC is gradually clarified, hypoxia is becoming a key determinant and an important therapeutic target of pancreatic cancer. To adapt to the severe hypoxia environment, cells have changed their metabolic phenotypes to maintain their survival and proliferation. Enhanced glycolysis is the most prominent feature of cancer cells' metabolic reprogramming in response to hypoxia. It provides the energy source for hypoxic cancer cells (although it provides less than oxidative phosphorylation) and produces metabolites that can be absorbed and utilized by normoxic cancer cells. In addition, the uptake of glutamine and fatty acids by hypoxic cancer cells is also increased, which is also conducive to tumor progression. Their metabolites are pooled in the hexosamine biosynthesis pathway (HBP). As a nutrition sensor, HBP, in turn, can coordinate glucose and glutamine metabolism. Its end product, UDP-GlcNAc, is the substrate of protein post-translational modification (PTM) involved in various signaling pathways supporting tumor progression. Adaptive metabolic changes of cancer cells promote their survival and affect tumor immune cells in the tumor microenvironment (TME), which contributes to tumor immunosuppressive microenvironment and induces tumor immunotherapy resistance. Here, we summarize the hypoxic microenvironment, its effect on metabolic reprogramming, and its contribution to immunotherapy resistance in pancreatic cancer.

S-phase kinase-associated protein 2 (SKP2) is an oncogene and cell cycle regulator that specifically recognizes phosphorylated cell cycle regulator proteins and mediates their ubiquitination. Programmed cell death protein 4 (PDCD4) is a tumor suppressor gene that plays a role in cell apoptosis and DNA-damage response via interacting with eukaryotic initiation factor-4A (eIF4A) and P53. Previous research showed SKP2 may interact with PDCD4, however the relationship between SKP2 and PDCD4 is unclear. To validate the interaction between SKP2 and PDCD4, mass spectrometric analysis and reciprocal co-immunoprecipitation (Co-IP) experiments were performed. SKP2 stably overexpressed or knockdown breast cancer cell lines were established and western blot was used to detect proteins changes before and after radiation. In vitro and in vivo experiments were performed to verify whether SKP2 inhibits cell apoptosis and promotes DNA-damage response via PDCD4 suppression. SMIP004 was used to test the effect of radiotherapy combined with SKP2 inhibitor. We found that SKP2 remarkably promoted PDCD4 phosphorylation, ubiquitination and degradation. SKP2 promoted cell proliferation, inhibited cell apoptosis and enhanced the response to DNA-damage via PDCD4 suppression in breast cancer. SKP2 and PDCD4 showed negative correlation in human breast cancer tissues. Radiotherapy combine with SKP2 inhibitor SMIP004 showed significant inhibitory effects on breast cancer cells in vitro and in vivo. We identify PDCD4 as an important ubiquitination substrate of SKP2. SKP2 promotes breast cancer tumorigenesis and radiation tolerance via PDCD4 degradation. Radiotherapy combine with SKP2-targeted adjuvant therapy may improve breast cancer patient survival in clinical medicine.

Epithelial-mesenchymal transition (EMT) plays a crucial role in small airway fibrosis of patients with chronic obstructive pulmonary disease (COPD). Increasing evidence suggests that the urokinase plasminogen activator receptor (uPAR) is involved in the pathogenesis of COPD. Increased uPAR expression has been implicated in the promotion of EMT in numerous cancers; however the role of uPAR in EMT in small airway epithelial cells of patients with COPD remains unclear. In this study, we investigated the degree of EMT and uPAR expression in lung epithelium of COPD patients, and verified the effect of uPAR on cigarette smoke extract (CSE)-induced EMT in vitro. The expression of EMT biomarkers and uPAR was assessed in lung epithelium specimens from non-smokers (n = 25), smokers (n = 25) and non-smokers with COPD (n = 10) and smokers with COPD (n = 18). The role of uPAR on CSE-induced EMT in human small airway epithelial cells (HSAEpiCs) was assessed by silencing uPAR expression in vitro. Markers of active EMT and uPAR expression were significantly increased in the small airway epithelium of patients with COPD compared with controls. We also observed a significant correlation between uPAR and vimentin expression in the small airway epithelium. In vitro, CSE-induced EMT in HSAEpiCs was associated with high expression of uPAR, and targeted silencing of uPAR using shRNA inhibited CSE-induced EMT. Finally, we demonstrate that the PI3K/Akt signaling pathway is required for uPAR-mediated EMT in HSAEpiCs. A uPAR-dependent signaling pathway is required for CSE-induced EMT, which contributes to small airway fibrosis in COPD. We propose that increased uPAR expression in the small airway epithelium of patients with COPD participates in an active EMT process.

Pyroptosis is a type of programmed cell death characterized by the activation of inflammatory caspases and the cleavage of gasdermin proteins. Pyroptosis can suppress tumor development and induce antitumor immunity, and activating pyroptosis is a potential treatment strategy for cancer. To uncover approaches to harness the anticancer effects of pyroptosis, we aimed to identify regulators of pyroptosis in cancer. A CRISPR-Cas9 screen identified that loss of USP48, a deubiquitinating enzyme, significantly inhibited cell pyroptosis. USP48 promoted pyroptosis by stabilizing gasdermin E (GSDME). USP48 bound GSDME and removed K48-linked ubiquitination at positions K120 and K189. Clinical tissue testing confirmed that the expression of USP48 positively correlated with GSDME and pyroptosis-related factors. Single-cell sequencing showed that the functions of T cells and tumor-associated macrophages in the tumor microenvironment were inhibited after USP48 knockout. Finally, overexpression of USP48 enhanced the therapeutic efficacy of programmed cell death protein 1 inhibitors in tumors in mouse models. Together, these findings define a pyroptosis regulation pathway and indicate that pharmacologic activation of USP48 may provide an effective strategy to sensitize cancer cells to pyroptosis and improve response to immunotherapy. Significance: USP48 promotes pyroptosis by deubiquitinating GSDME and enhances antitumor immunity, indicating that increasing USP48 activity may be a future therapeutic strategy for treating cancer.