ITCH facilitates proteasomal degradation of TXNIP in hypoxia‐ induced lung cancer cells

Abstract

Background Lung cancer (LC) is one of the most common cancers and a leading cause of cancer‐related deaths worldwide. In many pathological conditions, particularly in the tumor microenvironment, cells and tissues frequently exist in a hypoxic state. Here, we evaluated Itchy E3 ubiquitin protein ligase (ITCH) expression in LC cells following hypoxia treatment. Methods LC cell lines were treated with hypoxic condition. Cell migration, invasion, inflammation, reactive oxygen species (ROS) production, and apoptosis of LC cells were determined by wound healing assay, Transwell invasive assay, ELISA, DCFH‐DA staining, and flow cytometry, respectively. qPCR and WB were used to determine the expression of ITCH and TXNIP. Co‐IP was performed to assess the interaction between ITCH and TXNIP. Results ITCH expression was downregulated in LC cells under hypoxic conditions. Next, LC cells were subjected to hypoxic conditions and changes in cell viability and metastasis were determined. Hypoxic conditions resulted in increased migration and invasion abilities of LC cells. Intracellular reactive oxygen species (ROS) production, inflammation, and apoptosis were also promoted by hypoxia. We found that ITCH overexpression led to the proteasomal degradation of thioredoxin‐interacting protein (TXNIP), whereas the expression of the ITCH C830A mutant did not affect TXNIP levels in LC cells. The gain‐of‐function experiment demonstrated that migration, invasion, ROS generation, inflammation, and apoptosis of hypoxia‐conditioned LC cells were ameliorated by ITCH overexpression, whereas the ITCH C830A mutant did not cause any changes in these phenotypes. Furthermore, the contribution of TXNIP knockdown and ITCH overexpression to the hypoxia‐induced features in LC cells with ITCH C830A was found to be similar. Conclusion Our results suggest a novel mechanism underlying the changes in ITCH‐mediated malignant phenotypes of hypoxia‐conditioned LC cells via TXNIP.

Cyr61 Mediates Angiotensin II-Induced Podocyte Apoptosis via the Upregulation of TXNIP

“…There is an important role for TXNIP in apoptosis. Sun et al [ 28 ] found that TXNIP expression was significantly reduced in hepatocellular carcinoma tissues. Additionally, through mitochondria-mediated ROS production and activation of MAPK pathways, TXNIP overexpression inhibited hepatocellular carcinoma cell proliferation.…”

ITCH-Mediated Ubiquitylation of ITGB3 Promotes Cell Proliferation and Invasion of Ectopic Endometrial Stromal Cells in Ovarian Endometriosis

“…As a member of the E3 ubiquitin ligases, ITCH plays a vital role in tumorigenesis. When treated under hypoxic conditions, ITCH expression was downregulated in lung cancer (LC) cell lines, which resulted in increased migration and invasion abilities of LC cells [ 26 ]. In colorectal carcinoma, the loss of ITCH expression is associated with carcinogenesis, and ITCH might be involved in the Notch-1 pathway during colorectal carcinoma progression [ 27 ].…”

ITCH is a Prognostic Biomarker and Immune Infiltrates in Lung Squamous Cell Adenocarcinoma

“…In triple negative breast cancer (TNBC), the nuclear localization of ITCH makes TNBC cells have DDR inhibition to counteract replication stress and increase the survival rate and growth potential of cancer cells [42]. In lung adenocarcinoma, ITCH promotes the metastasis of lung cancer cells under hypoxia [13]. In this study, we focused on the treatment resistance subgroup of lung squamous cell carcinoma.…”

“…In addition to its effect on Treg cells, ITCH can also inhibit the activation of T cell antigen receptor (TCR), which is an important way for T cells to exert anti-tumor effect [12]. In lung cancer, previous studies have shown that in lung adenocarcinoma, ITCH promotes the metastasis of lung cancer cells under hypoxia [13], but 82 there is no report of ITCH function in lung squamous cell carcinoma.…”