Inhibition of autophagy initiation : A novel strategy for oral squamous cell carcinomas
Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved..
BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most common forms of oral cancer and is known to have poor prognostic outcomes. Autophagy is known to be associated with aggressive tumor biology of OSCC. Hence, this study aimed to develop a novel therapeutic strategy against OSCC by targeting the autophagic pathway.
METHODS: Immunoblotting, and confocal microscopy were used to examine the effect of tumor microenvironmental stressors on the autophagy activity. Cellular proliferation and migration assays were performed to assess the anti-cancer activity of standard chemotherapy and autophagy initiation inhibitors, either alone or in combination. High resolution mass-spectrometry based proteomic analysis was utilized to understand the mechanisms behind chemoresistance in OSCC models. Finally, immunohistochemistry was performed to determine associations between autophagy markers and clinicopathological characteristics.
RESULTS: Tumor microenvironmental stressors were shown to induce autophagy activity in OSCC cell lines. Novel combinations of chemotherapy and autophagy inhibitors as well as different classes of autophagy inhibitors were identified. Combination of MRT68921 and SAR405 demonstrated marked synergy in their anti-proliferative activity and also showed synergy with chemotherapy in chemoresistant OSCC cell models. Autophagy was identified as one of the key pathways involved in mediating chemoresistance in OSCC. Furthermore, TGM2 was identified as a key upstream regulator of chemoresistance in OSCC models. Finally, positive staining for autophagosome marker LC3 was shown to be associated with low histological grade OSCC.
CONCLUSION: In conclusion, this study identified a combination of novel autophagy inhibitors which can potently inhibit proliferation of both chemosensitive as well as chemoresistant OSCC cells and could be developed as a novel therapy against advanced OSCC tumors.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:1871 |
|---|---|
| Enthalten in: |
Biochimica et biophysica acta. Molecular cell research - 1871(2024), 2 vom: 01. Feb., Seite 119627 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Abd El-Aziz, Yomna S [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Autophagy |
|---|
| Anmerkungen: |
Date Completed 15.01.2024 Date Revised 27.02.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.bbamcr.2023.119627 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM364551275 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM364551275 | ||
| 003 | DE-627 | ||
| 005 | 20240229170416.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.bbamcr.2023.119627 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1310.xml |
| 035 | |a (DE-627)NLM364551275 | ||
| 035 | |a (NLM)37963518 | ||
| 035 | |a (PII)S0167-4889(23)00200-8 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Abd El-Aziz, Yomna S |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Inhibition of autophagy initiation |b A novel strategy for oral squamous cell carcinomas |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 15.01.2024 | ||
| 500 | |a Date Revised 27.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most common forms of oral cancer and is known to have poor prognostic outcomes. Autophagy is known to be associated with aggressive tumor biology of OSCC. Hence, this study aimed to develop a novel therapeutic strategy against OSCC by targeting the autophagic pathway | ||
| 520 | |a METHODS: Immunoblotting, and confocal microscopy were used to examine the effect of tumor microenvironmental stressors on the autophagy activity. Cellular proliferation and migration assays were performed to assess the anti-cancer activity of standard chemotherapy and autophagy initiation inhibitors, either alone or in combination. High resolution mass-spectrometry based proteomic analysis was utilized to understand the mechanisms behind chemoresistance in OSCC models. Finally, immunohistochemistry was performed to determine associations between autophagy markers and clinicopathological characteristics | ||
| 520 | |a RESULTS: Tumor microenvironmental stressors were shown to induce autophagy activity in OSCC cell lines. Novel combinations of chemotherapy and autophagy inhibitors as well as different classes of autophagy inhibitors were identified. Combination of MRT68921 and SAR405 demonstrated marked synergy in their anti-proliferative activity and also showed synergy with chemotherapy in chemoresistant OSCC cell models. Autophagy was identified as one of the key pathways involved in mediating chemoresistance in OSCC. Furthermore, TGM2 was identified as a key upstream regulator of chemoresistance in OSCC models. Finally, positive staining for autophagosome marker LC3 was shown to be associated with low histological grade OSCC | ||
| 520 | |a CONCLUSION: In conclusion, this study identified a combination of novel autophagy inhibitors which can potently inhibit proliferation of both chemosensitive as well as chemoresistant OSCC cells and could be developed as a novel therapy against advanced OSCC tumors | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Autophagy | |
| 650 | 4 | |a Autophagy inhibitors | |
| 650 | 4 | |a Chemotherapy resistance | |
| 650 | 4 | |a Oral squamous cell carcinoma | |
| 650 | 4 | |a Proteomics | |
| 650 | 4 | |a Tumor microenvironment stress | |
| 700 | 1 | |a McKay, Matthew J |e verfasserin |4 aut | |
| 700 | 1 | |a Molloy, Mark P |e verfasserin |4 aut | |
| 700 | 1 | |a McDowell, Betty |e verfasserin |4 aut | |
| 700 | 1 | |a Moon, Elizabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Sioson, Loretta |e verfasserin |4 aut | |
| 700 | 1 | |a Sheen, Amy |e verfasserin |4 aut | |
| 700 | 1 | |a Chou, Angela |e verfasserin |4 aut | |
| 700 | 1 | |a Gill, Anthony J |e verfasserin |4 aut | |
| 700 | 1 | |a Jansson, Patric J |e verfasserin |4 aut | |
| 700 | 1 | |a Sahni, Sumit |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Biochimica et biophysica acta. Molecular cell research |d 2017 |g 1871(2024), 2 vom: 01. Feb., Seite 119627 |w (DE-627)NLM264216326 |x 1879-2596 |7 nnns |
| 773 | 1 | 8 | |g volume:1871 |g year:2024 |g number:2 |g day:01 |g month:02 |g pages:119627 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.bbamcr.2023.119627 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 1871 |j 2024 |e 2 |b 01 |c 02 |h 119627 | ||