Local anesthetic lidocaine-inducible gene, growth differentiation factor-15 suppresses the growth of cancer cell lines

Abstract

Administration of local anesthetics, such as lidocaine, in the perioperative period improves outcomes of cancer patients. However, its precise mechanism is still unresolved. The growth of human cancer cell lines, including HeLa cells, are suppressed by lidocaine treatment. We identified that growth differentiation factor-15 (GDF-15) was commonly upregulated in lidocaine-treated cancer cell lines. GDF-15 is a divergent member of the transforming growth factor-β (TGF-β) superfamily and it is produced as an unprocessed pro-protein form and then cleaved to generate a mature form. In lidocaine-treated HeLa cells, increased production of GDF-15 in the endoplasmic reticulum (ER) was observed and unprocessed pro-protein form of GDF-15 was secreted extracellularly. Further, lidocaine induced apoptosis and apoptosis-inducible Tribbles homologue 3 (TRIB3) was also commonly upregulated in lidocaine-treated cancer cell lines. In addition, transcription factor C/EBP homologous protein (CHOP), which is a positive regulator of not only GDF-15 but TRIB3 was also induced by lidocaine. Lidocaine-induced growth suppression and apoptosis was suppressed by knockdown of GDF-15 or TRIB3 expression by small interference RNA (siRNA). These observations suggest that lidocaine suppresses the growth of cancer cells through increasing GDF-15 and TRIB3 expression, suggesting its potential application as cancer therapy.

Growth Differentiation Factor 15 (GDF15) Expression in the Heart After Myocardial Infarction and Cardioprotective Effect of Pre-Ischemic rGDF15 Administration

“…It has been proposed that catecholamines, released during acute myocardial or cerebral ischemia, may remotely induce GDF15 secretion 18 . In a recent study, local anaesthetics such as lidocaine were shown to upregulate GDF15 production in HeLa cultured cells 19 , suggesting lidocaine use in our surgical procedure could contribute to the GDF15 secretion observed in both I/R and Sham rats. Additionally, two studies indicate that coronary artery bypass grafting in patients increases GDF15 plasma level by 2.5-or 3-fold compared to anaesthesia induction level 20,21 .…”

Growth/differentiation factor 15 (GDF15) expression in the heart after myocardial infarction and cardioprotective effect of pre-ischemic rGDF15 administration

“…It has been proposed that catecholamines, released during acute myocardial or cerebral ischemia, may remotely induce GDF15 secretion 28 . In a recent study, local anaesthetics such as lidocaine were shown to upregulate GDF15 production in HeLa cultured cells 38 , suggesting that lidocaine use in our surgical procedure may have contributed to the GDF15 secretion observed in both I/R and sham rats. Additionally, two studies indicate that coronary artery bypass grafting in patients increases GDF15 plasma level by 2.5- or 3-fold compared to anaesthesia induction level 39 , 40 .…”

Local anesthetic lidocaine induces growth suppression of HeLa cells by decreasing and changing the cellular localization of the proliferation marker Ki‐67

“…Importantly, MKI67 gene encoding Ki-67 is the target for E2F (Sun & Kaufman, 2018). Our RNA sequencing analysis (RNA-seq) using human cancer cell lines involving HeLa cells revealed that Ki-67 was commonly downregulated by lidocaine treatment (sequence data are available from ArrayExpress under the accession number E-MTAB-11320, https://www.ebi.ac.uk/ arrayexpress/experiments/E-MTAB-11320/), suggesting that lidocaine might function as an antitumor drug through regulating Ki-67 expression at transcriptional level in addition to posttranslational levels such as via the proteasome pathway (Haraguchi-Suzuki et al, 2022).…”