Knockdown of NUPR1 Enhances the Sensitivity of Non-small-cell Lung Cancer Cells to Metformin by AKT Inhibition

• Published in: Anticancer research Vol. 42; no. 7; pp. 3475 - 3481
• Main Authors: KIM, YU JIN, HONG, SUNG-EUN, JANG, SE-KYEONG, PARK, KI SOO, KIM, CHUN-HO, PARK, IN-CHUL, JIN, HYEON-OK
• Format: Journal Article
• Language: English
• Published: Athens International Institute of Anticancer Research 01.07.2022
• Subjects: Activating transcription factor 4; AKT protein; Anticancer properties; Antidiabetics; Antitumor activity; Cell activation; Cell viability; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Gene expression; Ionizing radiation; Kinases; Lung cancer; Metformin; Non-small cell lung carcinoma; Polymerase chain reaction; Protein-serine/threonine kinase; Reverse transcription; Sensitivity enhancement; Small cell lung carcinoma; Transcription activation
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.15834

Background/Aim: Metformin is a widely used drug for type 2 diabetes mellitus and has recently attracted broad attention for its therapeutic effects on many cancers. This study aimed to investigate the molecular mechanism of metformin's anticancer activity. Materials and Methods: Cell viability was measured by MTT assay. Gene and protein expression levels were determined by reverse transcription-polymerase chain reaction and western blot analyses, respectively. Results: Metformin and phenformin markedly induced NUPR1 expression in a dose- and time-dependent manner in H1299 non-small-cell lung cancer (NSCLC) cells. The silencing of NUPR1 in H1299 NSCLC cells enhanced cell sensitivity to metformin or ionizing radiation. Our previous report showed that metformin induces AKT serine/threonine kinase (AKT) activation in an activating transcription factor 4 (ATF4)-dependent manner and that the inhibition of AKT promotes cell sensitivity to metformin in H1299 NSCLC cells. Interestingly, ATF4-induced AKT activation in H1299 NSCLC cells treated with metformin was suppressed by the knockdown of NUPR1. Conclusion: Targeting NUPR1 could enhance the sensitivity of H1299 NSCLC cells to metformin by AKT inhibition.