CNR1 may reverse progesterone-resistance of endometrial cancer through the ERK pathway

Biochem Biophys Res Commun. 2021 Apr 9:548:148-154. doi: 10.1016/j.bbrc.2021.02.038. Epub 2021 Feb 25.


Endocrine therapy is a promising treatment for endometrial cancer (EC) that preserves fertility, however, progesterone-resistance is currently the major challenges. The Cancer Genome Atlas (TCGA) database analysis showed that CNR1 was closely have a negative correlation with overall survival (OS) and relapse-free survival (RFS) in endometrial cancer. To explore the role of CNR1 in progesterone resistance and possible molecular regulation mechanism, we established stable progesterone-resistant cell lines (IshikawaPR) via progesterone tolerance of ordinary cancer cells (Ishikawa). The difference of CNR1 level in two cell lines was assessed by MTT, RT-PCR, Western blot, immunofluorescence. Then, lentiviruses constructed CNR1-knockdown with GV248 as the tool vector were used to transfect IshikwaPR cells, and the changes of biological behavior and progesterone sensitivity was verified respectively through plate cloning experiment, EdU assay, flow cytometry cycle analysis, transwell, Scratch test, etc. We founded after CNR1 was knocked down, the proliferative activity and ability to migrate of IshikawaPR cells decreased, progesterone-response sensitivity could be improved. Moreover, knockdown of CNR1 can also down-regulate ERK and NFκ B expression and activation. Furthermore, subcutaneous xenograft in nude mice was tested similarly in vivo. The above datas suggest that targeting CNR1 may reverse the progesterone resistance in endometrial cancer and may coordinate the role of ERK pathway activation.

Keywords: CNR1; ERK pathway; Endometrial cancer; Progesterone resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Endometrial Neoplasms / genetics
  • Endometrial Neoplasms / metabolism*
  • Endometrial Neoplasms / pathology*
  • Endometrium / abnormalities*
  • Endometrium / metabolism
  • Endometrium / pathology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • Humans
  • MAP Kinase Signaling System* / drug effects
  • Medroxyprogesterone / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics
  • Uterine Diseases / genetics
  • Uterine Diseases / metabolism*
  • Uterine Diseases / pathology


  • CNR1 protein, human
  • Receptor, Cannabinoid, CB1
  • Medroxyprogesterone

Supplementary concepts

  • Progesterone Resistance