Cigarette smoke extract promotes metastasis and oxaliplatin resistance in colon adenocarcinoma through GDF15/ERBB2/AKT pathway.

Abstract

Background: Colon adenocarcinoma (COAD) exhibits high mortality due to metastasis and oxaliplatin (L-OHP) resistance. Cigarette, an established environmental risk factor, is linked to poor prognosis in COAD, yet the underlying molecular mechanisms have not been explored. Growth differentiation factor 15 (GDF15) can promote the occurrence and development of tumors. Here, we identified that GDF15 as a crucial mediator of cigarette smoke promoting the development of COAD.

Methods: Cox regression and Kaplan-Meier analyses were utilized to evaluate association between smoking history and prognosis of COAD patients. HT29 and HCT116 cells were chronically exposed to cigarette smoke extract (CSE) to evaluate migration, invasion and L-OHP resistance via transwell, wound healing, CCK-8, and flow cytometry. Bioinformatics analysis was utilized to study the association between GDF15 expression, smoking history and prognosis of COAD. GDF15 overexpression/knockdown models were established to study the effect of cigarette-induced GDF15 on COAD metastasis and chemotherapy resistance. RNA sequencing, co-immunoprecipitation (Co-IP) and inhibitor treatment were utilized to analyze GDF15-mediated ERBB2/AKT/SLC7A11 signaling. Nude mice xenografts with CSE-exposed or GDF15-knockdown cells were used to assess the effect of cigarette-induced GDF15 on L-OHP resistance in vivo.

Results: Smoking history was correlated with reduced overall survival (OS) in COAD patients (p = 0.0016). Chronic CSE exposure enhanced migration and invasion via epithelial-mesenchymal transition (EMT) and conferred L-OHP resistance. Cigarette smoke can elevate GDF15 expression in COAD and high GDF15 predicted poor OS and progression-free survival (PFS) in chemotherapy-treated cohorts. Functional experiments showed that CSE-induced GDF15 promoted COAD metastasis and L-OHP resistance. RNA-sequence showed that GDF15-related genes were significantly enriched in AKT and glutathione metabolic pathways. Mechanically, GDF15 can bind to ERBB2 and activate ERBB2/AKT phosphorylation, upregulate SLC7A11, and increase glutathione (GSH) levels, driving L-OHP resistance and metastasis. In vivo CSE-exposed xenografts showed reduced L-OHP sensitivity via GDF15.

Conclusions: CSE promoted COAD metastasis and L-OHP resistance by upregulating GDF15, which activated the ERBB2/AKT/SLC7A11 axis. Targeting GDF15 may offer therapeutic potential to overcome cigarette-aggravated COAD progression.