Liver kinase B1 (LKB1) is a tumor suppressor that functions as master regulator of cell growth, metabolism, survival, and polarity. Patients with NSCLC possessing mutated LKB1 respond to chemotherapy differently from those with wild-type LKB1. Gambogic acid (GA), a small molecule from natural product, has been established as an anti-tumor agent due to its potent activity and low toxicity. Here, we find out that NSCLC cells with wild-type LKB1 are more sensitive to GA in vitro and in vivo. Mechanistic studies pinpoint that the selective inhibition of mTOR signaling confers the stronger suppression of NSCLC in presence of wild-type LKB1, which is involved in the enhancement of p-AMPK. Further studies reveal that GA increases p-AMPK levels through up-regulation of E-cadherin associated with LKB1. In addition, induction of E-cadherin by GA may be through down-regulation of ZEB1, which is independent with LKB1 status. Hence, our findings support that enhanced E-cadherin by GA cooperates LKB1, leading to up-regulation of p-AMPK, and thus blocking of mTOR signaling pathway, which provide theoretical foundation for utilization of GA as a potential targeted drug against NSCLC harboring wild-type LKB1.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bcp.2019.113635 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
LKB1 dictates sensitivity to immunotherapy through Skp2-mediated ubiquitination of PD-L1 protein in non-small cell lung cancer.
J Immunother Cancer
December 2024
Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
Background: Loss-of-function mutations of (, also termed as ()) are frequently detected in patients with non-small cell lung cancer (NSCLC). The mutant NSCLC was refractory to almost all the antitumor treatments, including programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy. Unfortunately, mechanisms underlying resistance to immunotherapy are not fully understood.
View Article and Find Full Text PDFSensory neuron LKB1 mediates ovarian and reproductive function.
Sci Rep
November 2024
Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies (CAPS), The University of Texas at Dallas, Richardson, TX, 75080, USA.
Treatments for reproductive disorders in women consist of hormone replacement therapy, which have negative side effects that impact health, spurring the need to understand new mechanisms to employ new therapeutic strategies. Bidirectional communication between sensory neurons and the organs they innervate is an emerging area of interest in tissue physiology with a relevance in reproductive disorders. We hypothesized that the metabolic activity of sensory neurons has a profound effect on reproductive phenotypes.
View Article and Find Full Text PDFHyper-Interferon Sensitive Influenza Induces Adaptive Immune Responses and Overcomes Resistance to Anti-PD-1 in Murine Non-Small Cell Lung Cancer.
Cancer Immunol Res
December 2024
Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Despite recent advances in immunotherapy with immune checkpoint inhibitors, many patients with non-small cell lung cancer (NSCLC) fail to respond or develop resistance after an initial response. In situ vaccination (ISV) with engineered viruses has emerged as a promising antigen-agnostic strategy that can both condition the tumor microenvironment and augment antitumor T-cell responses to overcome immune resistance. We engineered a live attenuated viral vaccine, hyper-IFN-sensitive (HIS) virus, by conducting a genome-wide functional screening and introducing eight IFN-sensitive mutations in the influenza genome to enhance host IFN response.
View Article and Find Full Text PDFCachexia is a wasting syndrome comprised of adipose, muscle, and weight loss observed in cancer patients. Tumor loss-of-function mutations in , a regulator of the energy sensor AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are associated with cancer-related weight loss in NSCLC patients. Here we characterized the relevance of the NSCLC-associated cachexia factor growth differentiation factor 15 (GDF15) in several patient-derived and genetically engineered -mutant NSCLC cachexia lines.
View Article and Find Full Text PDFGenome-wide CRISPR screens in spheroid culture reveal that the tumor suppressor LKB1 inhibits growth via the PIKFYVE lipid kinase.
Proc Natl Acad Sci U S A
May 2024
Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10021.
Article Synopsis
- * To better understand how LKB1 suppresses cell growth, researchers created a specific cell culture model and conducted genome-wide CRISPR screenings, discovering that LKB1 partially achieves this by activating the PIKFYVE lipid kinase.
- * The study also revealed that LKB1 inhibits growth by promoting the internalization of the EGFR protein in a way that depends on PIKFYVE, using both chemical inhibitors and a special reporter to observe these effects.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!