Knockdown of Atg7 Induces Nuclear-LC3 Dependent Apoptosis and Augments Chemotherapy in Colorectal Cancer Cells

Autor: Anna-Lena Scherr, Henning Schulze-Bergkamen, Benjamin Goeppert, Nathalie Schmitt, Adam Jassowicz, Georg Gdynia, Anna Pató, Bruno Köhler, Dirk Jäger, Lars Ismail, Lasse Neukirch, Paula Hoffmeister, Christin Elssner
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
medicine.disease_cause
Autophagy-Related Protein 7
lcsh:Chemistry
0302 clinical medicine
LC3
lcsh:QH301-705.5
Spectroscopy
Cells
Cultured
medicine.diagnostic_test
Chemistry
apoptosis
General Medicine
Computer Science Applications
030220 oncology & carcinogenesis
Beclin-1
Fluorouracil
Colorectal Neoplasms
Atg7
HT29 Cells
Microtubule-Associated Proteins
Programmed cell death
autophagy
Cell Survival
colorectal cancer
Antineoplastic Agents
Adenocarcinoma
Irinotecan
Catalysis
Article
Flow cytometry
Inorganic Chemistry
03 medical and health sciences
Downregulation and upregulation
medicine
Humans
Viability assay
Physical and Theoretical Chemistry
Molecular Biology
Organic Chemistry
Autophagy
digestive system diseases
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
Cell culture
Apoptosis
Drug Resistance
Neoplasm
Cancer research
Carcinogenesis
Zdroj: International Journal of Molecular Sciences
Volume 21
Issue 3
International Journal of Molecular Sciences, Vol 21, Iss 3, p 1099 (2020)
ISSN: 1422-0067
Popis: Autophagy is a catabolic process that enables cells to degrade obsolete content and refuel energy depots. In colorectal cancer (CRC) autophagy has been shown to promote tumorigenesis through energy delivery in the condition of uncontrolled proliferation. With this study, we aimed at evaluating whether autophagy sustains CRC cell viability and if it impacts therapy resistance. Initially, a colorectal cancer tissue micro array, containing mucosa (n = 10), adenoma (n = 18) and adenocarcinoma (n = 49) spots, was stained for expression of essential autophagy proteins LC3b, Atg7, p62 and Beclin-1. Subsequently, central autophagy proteins were downregulated in CRC cells using siRNA technology. Viability assays, flow cytometry and immunoblotting were performed and three-dimensional cell culture was utilized to study autophagy in a tissue mimicking environment. In our study we found an upregulation of Atg7 in CRC. Furthermore, we identified Atg7 as crucial factor within the autophagy network for CRC cell viability. Its disruption induced cell death via triggering apoptosis and in combination with conventional chemotherapy it exerted synergistic effects in inducing CRC cell death. Cell death was strictly dependent on nuclear LC3b, since simultaneous knockdown of Atg7 and LC3b completely restored viability. This study unravels a novel cell death preventing function of Atg7 in interaction with LC3b, thereby unmasking a promising therapeutic target in CRC.
Databáze: OpenAIRE
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