FOXO1 Suppression is a Determinant of Acquired Lapatinib-Resistance in HER2-Positive Gastric Cancer Cells Through MET Upregulation
- Author:
Jinju PARK
1
;
Yiseul CHOI
;
Young San KO
;
Younghoon KIM
;
Jung Soo PYO
;
Bo Gun JANG
;
Min A KIM
;
Jae Seon LEE
;
Mee Soo CHANG
;
Jong Wan PARK
;
Byung Lan LEE
Author Information
- Publication Type:Original Article
- Keywords: Stomach neoplasms; ErbB-2 receptor; Drug resistance; Lapatinib; Human FOXO1 protein; Human MET protein
- MeSH: Blotting, Western; Cell Line; Cisplatin; Down-Regulation; Drug Resistance; Gentian Violet; Humans; In Vitro Techniques; Luciferases; Parents; Receptor, Epidermal Growth Factor; Receptor, ErbB-2; RNA Interference; Stomach Neoplasms; Transfection; Up-Regulation
- From:Cancer Research and Treatment 2018;50(1):239-254
- CountryRepublic of Korea
- Language:English
- Abstract: PURPOSE: Lapatinib is a candidate drug for treatment of trastuzumab-resistant, human epidermal growth factor receptor 2 (HER2)–positive gastric cancer (GC). Unfortunately, lapatinib resistance renders this drug ineffective. The present study investigated the implication of forkhead box O1 (FOXO1) signaling in the acquired lapatinib resistance in HER2-positive GC cells. MATERIALS AND METHODS: Lapatinib-resistant GC cell lines (SNU-216 LR2-8) were generated in vitro by chronic exposure of lapatinib-sensitive, HER2-positive SNU-216 cells to lapatinib. SNU-216 LR cells with FOXO1 overexpression were generated by stable transfection of a constitutively active FOXO1 mutant (FOXO1A3). HER2 and MET in SNU-216 LR cells were downregulated using RNA interference. The sensitivity of GC cells to lapatinib and/or cisplatin was determined by crystal violet assay. In addition, Western blot analysis, luciferase reporter assay and reverse transcription–polymerase chain reaction were performed. RESULTS: SNU-216 LR cells showed upregulations of HER2 and MET, but downregulation of FOXO1 compared to parental SNU-216 cells. FOXO1 overexpression in SNU-216 LR cells significantly suppressed resistance to lapatinib and/or cisplatin. In addition, FOXO1 negatively controlled HER2 and MET at the transcriptional level and was negatively controlled by these molecules at the post-transcriptional level. A positive crosstalk was shown between HER2 and MET, each of which increased resistance to lapatinib and/or cisplatin. CONCLUSION: FOXO1 serves as an important linker between HER2 and MET signaling pathways through negative crosstalks and is a key regulator of the acquired lapatinib resistance in HER2-positive GC cells. These findings provide a rationale for establishing a novel treatment strategy to overcome lapatinib resistance in a subtype of GC patients.
