conglobatin and Esophageal-Neoplasms

Cancer cells are characterized by altered energetic metabolism with increasing glucose uptake. F806, a 16-membered macrodiolide analogue, has anti-tumour effects on oesophageal squamous cell carcinoma (ESCC) cells. However, its precise anti-tumour mechanism remains unclear. Here, metascape analysis of our previous quantitative proteomics data showed that F806 induced glucose starvation response and inhibited energy production in ESCC cells. The reduced glucose uptake and ATP production were further validated by the fluorescent methods, using glucose-conjugated bioprobe Glu-1-O-DCSN, and the bioluminescent methods, respectively. Consistently, under F806 treatment the AMP-activated protein kinase signalling was activated, and autophagy flux was promoted and more autophagosomes were formed. Moreover, live-cell imaging and immunofluorescence analysis showed that F806 induced GLUT1 plasma membrane dissociation and promoted its internalization and autolysosome accumulation and lysosome degradation. Furthermore, molecular docking studies demonstrated that F806 bound to GLUT1 with a comparable binding energy to that of GLUT1's direct interacting inhibitor cytochalasin B. Amino acid mutation was used to test which residues of GLUT1 may participate in F806 mediated-GLUT1 internalization and degradation, and results showed that Thr137, Asn411 and Trp388 were required for GLUT1 internalization and degradation, respectively. Taken together, these findings shed light on a novel anti-tumour mechanism of F806 by targeting and promoting GLUT1 internalization and further autolysosomal degradation.

Topics: Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Glucose; Glucose Transporter Type 1; Humans; Macrolides; Molecular Docking Simulation

The paucity of new drugs for the treatment of esophageal squamous cell carcinoma (ESCC) limits the treatment options. This study characterized the therapeutic efficacy and action mechanism of a novel natural macrolide compound F806 in human ESCC xenograft models and cell lines. F806 inhibited growth of ESCC, most importantly, it displayed fewer undesirable side effects on normal tissues in two human ESCC xenograft models. F806 inhibited proliferation of six ESCC cells lines, with the half maximal inhibitory concentration (IC50) ranging from 9.31 to 16.43 μM. Furthermore, F806 induced apoptosis of ESCC cells, contributing to its growth-inhibitory effect. Also, F806 inhibited cell adhesion resulting in anoikis. Mechanistic studies revealed that F806 inhibited the activation of β1 integrin in part by binding to a novel site Arg610 of β1 integrin, suppressed focal adhesion formation, decreased cell adhesion to extracellular matrix and eventually triggered apoptosis. We concluded that F806 would potentially be a well-tolerated anticancer drug by targeting β1 integrin, resulting in anoikis in ESCC cells.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Humans; Integrin beta1; Male; Mice; Mice, Nude; Oxazoles; Random Allocation; Xenograft Model Antitumor Assays