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JAK2/STAT3 inhibitor reduced 5-FU resistance and autophagy through ATF6-mediated ER stress

Lijuan Ma1, Youhui Wang1

  • 1The Affiliated People's Hospital of Ningbo University Integrated Chinese and Western Medicine Oncology, Ningbo City, China.

Journal of Receptor and Signal Transduction Research
|February 18, 2021
PubMed

Insights

Targeting the JAK2/STAT3 pathway can overcome 5-fluorouracil (5-FU) drug resistance in gastric cancer by modulating endoplasmic reticulum (ER) stress and autophagy via ATF6. This offers a potential strategy to improve chemotherapy efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Drug resistance, particularly to 5-fluorouracil (5-FU), significantly impedes gastric cancer treatment.
  • Endoplasmic reticulum (ER) stress and autophagy are implicated mechanisms in gastric cancer drug resistance.

Purpose of the Study:

  • To investigate the role of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway in 5-FU resistance in gastric cancer cells.
  • To elucidate the involvement of ER stress and autophagy, specifically the ATF6 pathway, in mediating this resistance.

Main Methods:

  • Utilized Western blot to analyze protein expression of drug resistance, autophagy, and ER stress markers in AGS/5-FU cells treated with JAK2/STAT3 inhibitors.
  • Employed luciferase reporter assays to assess ATF6 promoter activity and immunofluorescence to detect LC3B expression.
  • Investigated the regulatory role of the JAK2/STAT3 pathway on ER stress using ER stress inhibitors and ATF6 overexpression.

Main Results:

  • JAK2 or STAT3 inhibition altered protein expression, suppressed ATF6 promoter activity, and affected autophagy markers.
  • ATF6 overexpression reversed the effects of JAK2/STAT3 inhibition.
  • ER stress inhibition mimicked the effects of JAK2/STAT3 inhibition, indicating pathway involvement.

Conclusions:

  • The JAK2/STAT3 pathway regulates 5-FU resistance in gastric cancer by influencing ER stress and autophagy through ATF6.
  • Targeting the JAK2/STAT3 pathway presents a potential therapeutic strategy to overcome 5-FU resistance and enhance treatment sensitivity in gastric cancer.
  • This study provides novel molecular insights into gastric cancer 5-FU resistance mechanisms.
Keywords:
5-FUJAK2/STAT3 inhibitorautophagydrug resistanceendoplasmic reticulum stress

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