Mechanism of TFF3-dependent TWIST1 Upregulating TRIB3 to Promote Colorectal Cancer Metastasis / 肿瘤防治研究

Objective To investigate the effects of TFF3 overexpression on the proliferation, migration, and invasion ability of colorectal cancer HT29 cells and the mechanisms involved in cancer metastasis. Methods HT29 cells were transfected with pIRES2-TFF3, and the expression levels of mRNAs and proteins related to TFF3 gene, TWIST1/TRIB3 signaling pathway, and epithelial-mesenchymal transition (EMT) were detected by qRT-PCR and Western blot. The proliferation, migration, and invasion ability of HT29 cells were detected by the CCK-8, cell scratch, and Transwell assays. Changes in cell morphology after TFF3 overexpression were observed through transmission electron microscopy. Results After the HT29 cells were transfected with pIRES2-TFF3, the expression levels of TFF3 mRNA and protein significantly increased (P<0.01); cell proliferation, migration, and invasion were significantly enhanced (P<0.01); and the expression of related genes, such as TWIST1, TRIB3, Vimentin, and Snail were significantly upregulated. By contrast, the expression of E-cadherin significantly decreased (P<0.05). Various changes in cell morphology were observed after TFF3 overexpression, such as decrease in cell junctions, loss of cilia, formation of pseudopodia, and increase in fusiform cells. Conclusion TFF3 overexpression may promote EMT in colorectal cancer cells through the Twist1/TRIB3 signaling pathway, increase their metastatic potential, and accelerate the malignant progression of colorectal cancer.

c-MYC-mediated TRIB3/P62+ aggresomes accumulation triggers paraptosis upon the combination of everolimus and ginsenoside Rh2

The mammalian target of rapamycin (mTOR) pathway is abnormally activated in lung cancer. However, the anti-lung cancer effect of mTOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the mTOR inhibitor everolimus both in vitro and in vivo. Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2 (labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. Eve-Rh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased c-MYC mediated the accumulation of tribbles homolog 3 (TRIB3)/P62+ aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62+ aggresomes-triggered paraptosis and revealed a unique function of c-MYC.

TRIB3 promotes lung cancer cell survival and inhibits apoptosis through NRF2 activation / 药学学报

The nuclear transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) plays a crucial role in maintaining cellular redox homeostasis. The aberrant NRF2 signaling confers enhanced antioxidant capacity, which is linked to tumor progression and therapeutic resistance. The current study investigates the biological effects and molecular mechanism of tribbles homolog 3 (TRIB3), a stress-induced protein, in regulating cell survival and apoptosis in lung cancer. This study first performed the RNA sequencing data analysis with 576 lung adenocarcinoma patients from the cancer genome atlas (TCGA) database. The NRF2- antioxidant response element (ARE) signature was enriched in patients with high TRIB3 expression. Dual-luciferase reporter assay and real-time quantitative polymerase chain reaction (PCR) were used to confirm the effect of TRIB3 on the kelch-like ECH-associated protein-1 (KEAP1)-NRF2 pathway. Abrogation of TRIB3 impaired NRF2 transcriptional activity and reduced the expression of its target genes. Moreover, TRIB3 enhanced NRF2 stability via blocking KEAP1-NRF2 interaction. TRIB3-depletion promoted reactive oxygen species (ROS) production, restrained cell proliferation, and enhanced carboplatin-induced apoptosis. In addition, NRF2 overexpression recovered the tumor inhibition effect of TRIB3-depletion. Consistently, TRIB3 failed to modulate apoptosis in NRF2 depletion cells. In summary, this study shows that TRIB3 inhibits the KEAP1-NRF2 interaction and upregulates the transcriptional activity of NRF2, thereby promoting lung cancer cell proliferation and reducing the sensitivity to chemotherapy. Targeting the TRIB3-NRF2 signal axis may become a new strategy for ROS homeostasis and lung cancer treatment.

TRIB3‒GSK-3

Pulmonary fibrosis (PF) is a chronic, progressive, fatal interstitial lung disease with limited available therapeutic strategies. We recently reported that the protein kinase glycogen synthase kinase-3

Current study of trib3 and diseases / 中国药理学通报

TRIB3 is a pseudokinase that binds to a variety of proteins in eukaryotic cells and mediates the development of diabetes, cancer, cardiovascular diseases and nervous system diseases, but their mutual regulatory relationship and molecular mechanisms have not yet been elucidated. This article reviews the diseases and regulatory pathways involved in TRIB3, in or-der to provide clues and evidence for finding common molecular mechanisms of the pathogenesis of diabetes, cancer and cardiovascular diseases.

Progress of TRIB3 gene research / 中国基层医药

Tribbles homolog 3(TRIB3,also named TRB3,NIPK,and SKIP3)belongs to the tribbles family of pseudokinases,that were first identified in Drosophila to regulate cell division and migration.TRIB3 expression is upregulated by endoplasmic reticulum stress,hypoxia,and nutrient starvation.Previous studies showed that TRIB3 expression was closely related to the progression of type 2 diabetes mellitus,and that TRIB3 mediated apoptosis in islet beta cells,as well as insulin resistance.Recent studies suggested that TRIB3 is a potential oncogene,as evidenced by its elevated expression in colorectal cancer,breast cancer,liver cancer and other cancer tissues.

Roles of TRIB3 in unfolded protein response / 国际肿瘤学杂志

Endoplasmic reticulum stress in tumor cells is common,the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum can lead to unfolded protein response (UPR).Research shows that UPR can protect cells,reestablish endoplasmic reticulum function and homeostasis at initial stage,and can promote apoptotic at later stage.TRIB3 is one of the mammal pseudoprotein kinase family Tribbles,and plays an important pivotal role in UPR,which can not only promote apoptosis but also play a protective role.