Her2-Targeted Therapy Induces Autophagy in Esophageal Adenocarcinoma Cells

Abstract

Esophageal adenocarcinoma (EAC) is a highly lethal cancer type with an overall poor survival rate. Twenty to thirty percent of EAC overexpress the human epidermal growth factor receptor 2 (Her2), a transmembrane receptor tyrosine kinase promoting cell growth and proliferation. Patients with Her2 overexpressing breast and gastroesophageal cancer may benefit from Her2 inhibitors. Therapy resistance, however, is well documented. Since autophagy, a lysosome-dependent catabolic process, is implicated in cancer resistance mechanisms, we tested whether autophagy modulation influences Her2 inhibitor sensitivity in EAC. Her2-positive OE19 EAC cells showed an induction in autophagic flux upon treatment with the small molecule Her2 inhibitor Lapatinib. Newly generated Lapatinib-resistant OE19 (OE19 LR) cells showed increased basal autophagic flux compared to parental OE19 (OE19 P) cells. Based on these results, we tested if combining Lapatinib with autophagy inhibitors might be beneficial. OE19 P showed significantly reduced cell viability upon double treatment, while OE19 LR were already sensitive to autophagy inhibition alone. Additionally, Her2 status and autophagy marker expression (LC3B and p62) were investigated in a treatment-naïve EAC patient cohort (n = 112) using immunohistochemistry. Here, no significant correlation between Her2 status and expression of LC3B and p62 was found. Our data show that resistance to Her2-directed therapy is associated with a higher basal autophagy level, which is not per se associated with Her2 status. Therefore, we propose that autophagy may contribute to acquired resistance to Her2-targeted therapy in EAC, and that combining Her2 and autophagy inhibition might be beneficial for EAC patients.

Irisin ameliorates angiotensin II‐induced cardiomyocyte apoptosis through autophagy

“…Cardiomyocyte apoptosis induced by autophagy flux block is a relatively newly discovered signal transduction pathway (Feng et al, 2018). The expression of LC3II and P62 were increased after AngII treatment in the cardiomyocytes, and cardiomyocytes apoptosis was increased as well, indicating an increase in the production of autophagy and blockage in the autophagic flow with AngII (Janser et al, 2018). In this study, it was found that irisin In conclusion, irisin may reduce myocardial apoptosis by increasing autophagy activity and autophagy flux, and inhibiting the apoptosis signaling factor in myocardial cells damaged by AngII.…”

Assessing Autophagy in Archived Tissue or How to Capture Autophagic Flux from a Tissue Snapshot

“…Therefore, there is a lot of interest in using this type of samples for pre-clinical studies. The ATG proteins MAP1LC3B, p62/SQSMT1, Beclin-1 and LAMP2A are frequently stained and used to assess the status of autophagy [52,[147][148][149][150][151][152][153]. These proteins are unfortunately not specific to autophagy and therefore interpretation of autophagic activity based on ATG protein levels is still under discussion.…”

Profiles of autophagy-related genes in esophageal adenocarcinoma

“…Therefore, it's imperative to identify innovative methods and biomarkers for early stage detection along with new treatment strategies. Cumulative evidences showed that autophagy was involved in the pathogenesis of EAC and may provide bene ts for patients [8][9][10] .…”

“…Although the autophagy in the EAC has not been studied thoroughly, alterations in autophagy have been identi ed in several studies [11][12][13] . In addition, the autophagy-related genes (ARGs) and proteins including Beclin-1 and p62 have been already studied in EAC [8,10,14] . These studies demonstrated the critical roles of autophagy in the development of EAC and responses to therapy.…”