Oral Squamous Cell Carcinoma Cells with Acquired Resistance to Erlotinib Are Sensitive to Anti-Cancer Effect of Quercetin via Pyruvate Kinase M2 (PKM2)

Cells. 2023 Jan 1;12(1):179. doi: 10.3390/cells12010179.

Abstract

Oral squamous cell carcinoma (OSCC) frequently carries high epidermal growth factor receptor (EGFR) expression. Erlotinib, a small molecule tyrosine kinase inhibitor (TKI), is an effective inhibitor of EGFR activity; however, resistance to this drug can occur, limiting therapeutic outcomes. Therefore, in the current study, we aimed to unveil key intracellular molecules and adjuvant reagents to overcome erlotinib resistance. First, two HSC-3-derived erlotinib-resistant cell lines, ERL-R5 and ERL-R10, were established; both exhibited relatively higher growth rates, glucose utilization, epithelial-mesenchymal transition (EMT), and invasiveness compared with parental cells. Cancer aggressiveness-related proteins, such as N-cadherin, Vimentin, Twist, MMP-2, MMP-9, and MMP-13, and the glycolytic enzymes PKM2 and GLUT1 were upregulated in ERL-R cells. Notably, ERL-R cells were sensitive to quercetin, a naturally-existing flavonol phytochemical with anti-cancer properties against various cancer cells. At a concentration of 5 μM, quercetin effectively arrested cell growth, reduced glucose utilization, and inhibited cellular invasiveness. An ERL-R5-derived xenograft mouse model confirmed the growth-inhibitory efficacy of quercetin. Additionally, knock-down of PKM2 by siRNA mimicked the effect of quercetin and re-sensitized ERL-R cells to erlotinib. Furthermore, adding quercetin blocked the development of erlotinib-mediated resistance by enhancing apoptosis. In conclusion, our data support the application of quercetin in anti-erlotinib-resistant OSCC and indicate that PKM2 is a determinant factor in erlotinib resistance and quercetin sensitivity.

Keywords: OSCC; PKM2; erlotinib; quercetin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Carcinoma, Squamous Cell* / drug therapy
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride / pharmacology
  • Erlotinib Hydrochloride / therapeutic use
  • Glucose
  • Head and Neck Neoplasms* / drug therapy
  • Humans
  • Lung Neoplasms* / pathology
  • Mice
  • Mouth Neoplasms* / drug therapy
  • Pyruvate Kinase
  • Quercetin / pharmacology
  • Quercetin / therapeutic use
  • Squamous Cell Carcinoma of Head and Neck / drug therapy

Substances

  • Erlotinib Hydrochloride
  • Quercetin
  • Pyruvate Kinase
  • ErbB Receptors
  • Glucose

Grants and funding

This research was funded by the Ministry of Science and Technology, Taiwan, grant number MOST 109-2320-B-309-002- and MOST 103-2320-B-039-031-MY3, and China Medical University, Taiwan, grant number CMU107-S-22 and CMU109-MF-53.