A CRAF/glutathione-S-transferase P1 complex sustains autocrine growth of cancers withKRASandBRAFmutations

This study shows that a vital component of the pathway CRAF is directly impacted by an end product of the cascade, glutathione transferases P1, driving a previously unrecognized autocrine cycle that sustains proliferation of mKRASand mBRAFcancer cells, independent of oncogenic stimuli

Yoshiro Niitsu; Yasushi Sato; Kunihiro Takanashi; Tsuyoshi Hayashi; Naoko Kubo-Birukawa; Fumiko Shimizu; Naoki Fujitani; Rai Shimoyama; Takehiro Kukitsu; Wataru Kurata; Yasuyuki Tashiro; Irving Listowsky

2020

Scholarcy highlights

  • The Ras/RAF/MEK/ERK pathway is an essential signaling cascade for various refractory cancers, such as those with mutant KRAS and BRAF
  • Among the isoenzymes tested in WT KRAS and mutant KRAS cells, only GSTP1 correlated with KRAS mutations
  • The study in a wider variety of malignant cell lines which included those with mKRAS or mBRAF and those without these mutations disclosed that GSTP1 expression was well defined in cells with mutations, whereas it was not detected in cells with WTKRAS/WTBRAF
  • The results reported here are consistent with the view that, in mKRAS cancers, there is a direct cause-and-effect relationship between mKRAS and GSTP1 expression and that the GSTP1CRAF interaction perpetuates an autocrine cycle that circumvents the primary growth signal
  • We suggest that activation as well as enhanced dimerization of CRAF occur upon GSTP1 binding to the receptor binding domain reported here which prevents this folding and opens dimerization capacity with other RAF family members
  • The suggestion that GSTP1 involves both dimer formation and activation of CRAF is consistent with previous reports, indicating that dimerization is a critical step for activation of RAF enzyme activity
  • The essential growth signaling CRAF/MER/ ERK cascade in cancers, such as those with mutant KRAS and mBRAF cells, can be controlled by specific interactions of CRAF with GSTP1 in the promotion of an autocrine growth cycle

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