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The ATF2-KNSTRN Axis Harnesses Lactate to Modulate MLH1/MSH2 Expression and Gemcitabine Resistance in Lung
Huanghui Wu1, Kun Han2, Biaolong Zheng1
1Internal Medicine Department of Oncology, Jinjiang Municipal Hospital, Jinjiang, China.
Abstract:
Gemcitabine (GEM) is a cornerstone of chemotherapy for lung adenocarcinoma (LUAD). However, acquired resistance severely limits its clinical efficacy, leading to relapse and metastasis. This study aims to investigate the role of KNSTRN in GEM resistance and its underlying molecular mechanisms in LUAD. Bioinformatics analysis revealed the expression levels of KNSTRN in LUAD tissues and the enriched pathways, and analyzed the prognostic impact of KNSTRN in LUAD, predicting the upstream transcription factor (TF) ATF2. The study examined the correlation and binding sites between KNSTRN and ATF2, as well as the expression of ATF2 in LUAD tissues. Molecular and cellular experiments were conducted to depict the binding relationship between ATF2 and KNSTRN and their expression within cells; to assess cell viability and IC50 values; to evaluate the expression of proteins related to the mismatch repair pathway, glycolytic pathway, and DNA damage markers; and to measure extracellular acidification rate, oxygen consumption rate, lactate production, and glucose consumption. Bioinformatics evidence pointed to ATF2 being the upstream TF for KNSTRN, with their expressions positively linked. High levels of ATF2 and KNSTRN were detected in LUAD tissues and cells, and high KNSTRN expression was associated with poor prognosis. KNSTRN promoted glycolysis and lactate accumulation, which in turn suppressed the expression of key MMR components MLH1 and MSH2, thereby impairing DNA damage repair capacity correlated positively with the expression of pivotal genes in these pathways. Molecular and cellular studies corroborated that KNSTRN overexpression enhances GEM resistance, a process that is thought to be mediated by increased lactate production and the regulation of mismatch repair pathways. Rescue experiments showed that the overexpression of KNSTRN reversed the effects of ATF2 silencing on LUAD cell GEM resistance. This study has uncovered a novel mechanism by which ATF2 activates KNSTRN, leading to increased lactate production and the downregulation of MLH1 and MSH2 expression, key components of the mismatch repair machinery, thereby promoting GEM resistance in LUAD. This discovery offers new insights for improving the efficacy of chemotherapy in LUAD.
Insights
This study reveals KNSTRN promotes gemcitabine resistance in lung adenocarcinoma by increasing lactate and downregulating DNA repair proteins MLH1 and MSH2, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Gemcitabine (GEM) is a key chemotherapy for lung adenocarcinoma (LUAD).
- Acquired resistance to GEM limits its clinical effectiveness, leading to disease relapse and metastasis.
- Understanding the mechanisms of GEM resistance is crucial for improving LUAD treatment outcomes.
Purpose of the Study:
- To investigate the role of KNSTRN in gemcitabine resistance in LUAD.
- To elucidate the molecular mechanisms underlying KNSTRN-mediated GEM resistance.
- To identify potential therapeutic targets for overcoming GEM resistance in LUAD.
Main Methods:
- Bioinformatics analysis of LUAD tissue expression data for KNSTRN and ATF2.
- Correlation analysis between KNSTRN and ATF2 expression and prognostic impact.
- Molecular and cellular experiments to assess cell viability, protein expression (MMR, glycolysis, DNA damage), and metabolic parameters (ECAR, OCR, lactate, glucose).
- Rescue experiments to validate the role of ATF2 and KNSTRN in GEM resistance.
Main Results:
- High expression of KNSTRN and its upstream transcription factor ATF2 was observed in LUAD tissues and cells, associated with poor prognosis.
- KNSTRN overexpression promoted glycolysis and lactate production, suppressing mismatch repair (MMR) components MLH1 and MSH2.
- This suppression impaired DNA damage repair capacity, leading to enhanced gemcitabine resistance in LUAD cells.
- ATF2 activation of KNSTRN was identified as a key driver of GEM resistance via metabolic reprogramming and MMR pathway dysregulation.
Conclusions:
- KNSTRN plays a critical role in promoting gemcitabine resistance in LUAD.
- The ATF2-KNSTRN axis drives GEM resistance through increased lactate production and downregulation of MLH1/MSH2, impairing DNA repair.
- Targeting the ATF2-KNSTRN pathway presents a potential strategy to enhance gemcitabine efficacy in LUAD treatment.
