Inhibition of autophagy initiation: A novel strategy for oral squamous cell carcinomas

Yomna S Abd El-Aziz; Matthew J McKay; Mark P Molloy; Betty McDowell; Elizabeth Moon; Loretta Sioson; Amy Sheen; Angela Chou; Anthony J Gill; Patric J Jansson; Sumit Sahni

doi:10.1016/j.bbamcr.2023.119627

Inhibition of autophagy initiation: A novel strategy for oral squamous cell carcinomas

Biochim Biophys Acta Mol Cell Res. 2024 Feb;1871(2):119627. doi: 10.1016/j.bbamcr.2023.119627. Epub 2023 Nov 12.

Authors

Affiliations

¹ Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt.
² Kolling Institute of Medical Research, University of Sydney, Australia.
³ NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia.
⁴ Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia.
⁵ Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia.
⁶ Kolling Institute of Medical Research, University of Sydney, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
⁷ Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Australia; Kolling Institute of Medical Research, University of Sydney, Australia. Electronic address: sumit.sahni@sydney.edu.au.

PMID: 37963518
DOI: 10.1016/j.bbamcr.2023.119627

Abstract

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.

Keywords: Autophagy; Autophagy inhibitors; Chemotherapy resistance; Oral squamous cell carcinoma; Proteomics; Tumor microenvironment stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autophagy
Carcinoma, Squamous Cell* / metabolism
Cell Line, Tumor
Head and Neck Neoplasms*
Humans
Mouth Neoplasms* / metabolism
Proteomics
Squamous Cell Carcinoma of Head and Neck / drug therapy