Lidocaine induces epithelial‑mesenchymal transition and aggravates cancer behaviors in non‑small cell lung cancer A549 cells

Wen-Hui Hsieh; Shu-Wei Liao; Shun-Ming Chan; Jin-De Hou; Szu-Yuan Wu; Bing-Ying Ho; Kung-Yen Chen; Yu-Ting Tai; Hsu-Wei Fang; Chih-Yuan Fang; Se-Yi Chen; Jui-An Lin

doi:10.3892/ol.2023.13932

Lidocaine induces epithelial‑mesenchymal transition and aggravates cancer behaviors in non‑small cell lung cancer A549 cells

Oncol Lett. 2023 Jun 27;26(2):346. doi: 10.3892/ol.2023.13932. eCollection 2023 Aug.

Authors

Wen-Hui Hsieh¹, Shu-Wei Liao², Shun-Ming Chan³, Jin-De Hou^{4

5}, Szu-Yuan Wu^{6

7

8

9

10

11}, Bing-Ying Ho^{12

13}, Kung-Yen Chen¹⁴, Yu-Ting Tai^{6

14

15}, Hsu-Wei Fang^{1

16}, Chih-Yuan Fang^{17

18}, Se-Yi Chen^{19

20}, Jui-An Lin^{5

6

15

21

22

23}

Affiliations

¹ Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei 10608, Taiwan, R.O.C.
² Department of Anesthesiology, Chi-Mei Medical Center, Tainan 71004, Taiwan, R.O.C.
³ Department of Anesthesiology, Tri-Service General Hospital and National Defense Medical Center, Taipei 11490, Taiwan, R.O.C.
⁴ Division of Anesthesiology, Hualien Armed Forces General Hospital, Hualien 97144, Taiwan, R.O.C.
⁵ Department of Anesthesiology, School of Medicine, National Defense Medical Center, Taipei 11490, Taiwan, R.O.C.
⁶ Center for Regional Anesthesia and Pain Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan, R.O.C.
⁷ Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan, R.O.C.
⁸ Big Data Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan 265501, Taiwan, R.O.C.
⁹ Division of Radiation Oncology, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan 265501, Taiwan, R.O.C.
¹⁰ Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan, R.O.C.
¹¹ Graduate Institute of Business Administration, Fu Jen Catholic University, Taipei 24205, Taiwan, R.O.C.
¹² Primo Biotechnology Co., Ltd., Taipei 10480, Taiwan, R.O.C.
¹³ Molecular Imaging Center, National Taiwan University, Taipei 10672, Taiwan, R.O.C.
¹⁴ Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan, R.O.C.
¹⁵ Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, R.O.C.
¹⁶ Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli 350, Taiwan, R.O.C.
¹⁷ Division of Oral and Maxillofacial Surgery, Department of Dentistry, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan, R.O.C.
¹⁸ School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan, R.O.C.
¹⁹ Department of Neurosurgery, Chung-Shan Medical University, Taichung 40201, Taiwan, R.O.C.
²⁰ School of Medicine, Chung-Shan Medical University, Taichung 40201, Taiwan, R.O.C.
²¹ Center for Regional Anesthesia and Pain Medicine, Chung Shan Medical University Hospital, Taichung 40201, Taiwan, R.O.C.
²² Department of Anesthesiology, School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan, R.O.C.
²³ Department of Anesthesiology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan, R.O.C.

Abstract

The effects of clinically relevant concentrations of lidocaine on epithelial-mesenchymal transition (EMT) and associated lung cancer behaviors have rarely been investigated. The aim of the present study was to assess the impact of lidocaine on EMT and its related phenomena, including chemoresistance. Lung cancer cell lines (A549 and LLC.LG) were incubated with various concentrations of lidocaine, 5-fluorouracil (5-FU) or both to test their effects on cell viability. Subsequently, the effects of lidocaine on various cell behaviors were assessed in vitro and in vivo using Transwell migration, colony-formation and anoikis-resistant cell aggregation assays, and human tumor cell metastasis in a chorioallantoic membrane (CAM) model quantitated by PCR analysis. Prototypical EMT markers and their molecular switch were analyzed using western blotting. In addition, a conditioned metastasis pathway was generated through Ingenuity Pathway Analysis. Based on these measured proteins (slug, vimentin and E-cadherin), the molecules involved and the alteration of genes associated with metastasis were predicted. Of note, clinically relevant concentrations of lidocaine did not affect lung cancer cell viability or alter the effects of 5-FU on cell survival; however, at this dose range, lidocaine attenuated the 5-FU-induced inhibitory effect on cell migration and promoted EMT. The expression levels of vimentin and Slug were upregulated, whereas the expression of E-cadherin was downregulated. EMT-associated anoikis resistance was also induced by lidocaine administration. In addition, portions of the lower CAM with a dense distribution of blood vessels exhibited markedly increased Alu expression 24 h following the inoculation of lidocaine-treated A549 cells on the upper CAM. Thus, at clinically relevant concentrations, lidocaine has the potential to aggravate cancer behaviors in non-small cell lung cancer cells. The phenomena accompanying lidocaine-aggravated migration and metastasis included altered prototypical EMT markers, anoikis-resistant cell aggregation and attenuation of the 5-FU-induced inhibitory effect on cell migration.

Keywords: chorioallantoic membrane; epithelial-mesenchymal transition; lidocaine; lung neoplasms; neoplasm metastasis.

Grants and funding

This work was supported by grants from the Hualien Armed Forces General Hospital, Taiwan (grant no. HAFGH-A_112001), the Chi Mei Medical Center, Taiwan (grant no. 108CM-TMU-13), and the Ministry of Science and Technology, Taiwan (grant no. MOST 108-2314-B-038-066-).