Role and regulation of GLUT1/3 during oral cancer progression and therapy resistance.

Abstract

OBJECTIVE:

This study aimed to determine whether glucose transporter-1/3 (GLUT1/3) increased expression could contribute to oral tumor severity. Furthermore, this study detected whether GLUT1/3 mRNA/protein was associated with oncogenic transcription factors (HIF1α, AP1 and NFκB) and whether by blocking GLUT1 along with cisplatin could sensitize drug-resistant OSCC cells.

DESIGN:

We used 120 post-operated human tissue samples, including 35 primary tumors (PT), 43 invasive tumors (N1-3), 17 recurrent chemoradiation-resistant tumors (RCRT), and 25 PT-adjacent normal tissues (AN). The cisplatin-resistant (CisR-SCC4/9) cells were generated using a drug escalation strategy from parental SCC4/9 cells. The BAY-876 treatment blocked GLUT1 in OSCC cells. Western Blot, Immunohistochemistry, and reverse transcription polymerase chain reaction (RT-PCR) were used to detect various proteins and mRNA. Cell survival was determined by MTT assay.

RESULTS:

GLUT1/3 expression was observed more in PT over AN tissue (PT > AN), N1-3 > PT, and .RCRT > PT. GLUT1 expression was maximum in the RCRT group and CisR-SCC4/9 cells over their parental counterpart, linked with tumor size (p=0.0037) and loco-regional invasiveness (p=0.0422). GLUT1/3 mRNA/protein was correlated (positively) with oncogenic transcription factors (TFs) like HIF1α, AP1 and NFκB. We found the degree of positive correlation of these TFs with GLUT1/3 was in the order c-Jun > HIF1α > Fra-2 > NFκB > c-Fos. Treatment of BAY-876 and cisplatin-induced cell death in both CisR-SCC4/9 cells, possibly by triggering apoptosis and autophagy.

CONCLUSION:

Collectively, our results demonstrated increased GLUT1/3 overexpression linked with oral tumor severity like invasion and therapy resistance, and it was powered mainly by c-Jun (AP1). Blocking GLUT1 receptors and cisplatin application can sensitize CisR-OSCC cells.

• Authors: Anjali Kumari, Arpita Jha, Anju Tiwari, Nidhi Nath, Ashok Kumar, Siddavaram Nagini, Rajakishore Mishra
• Journal: Archives of oral biology (Arch Oral Biol) Vol. 150 Pg. 105688 (Jun 2023) ISSN: 1879-1506 [Electronic] England
• PMID: 36989865 (Publication Type: Journal Article)
• Copyright: Copyright © 2023. Published by Elsevier Ltd.

Chemical References

• Cisplatin
• Glucose Transporter Type 1
• NF-kappa B
• RNA, Messenger

Topics

• Humans
• Cisplatin (pharmacology, therapeutic use)
• Glucose Transporter Type 1 (genetics, metabolism)
• Drug Resistance, Neoplasm
• Cell Line, Tumor
• Neoplasm Recurrence, Local
• Mouth Neoplasms (pathology)
• NF-kappa B (metabolism)
• RNA, Messenger (metabolism)
• Gene Expression Regulation, Neoplastic