A CRAF/glutathione-S-transferase P1 complex sustains autocrine growth of cancers with KRAS and BRAF mutations.

Abstract

The Ras/RAF/MEK/ERK pathway is an essential signaling cascade for various refractory cancers, such as those with mutant KRAS (mKRAS) and BRAF (mBRAF). However, there are unsolved ambiguities underlying mechanisms for this growth signaling thereby creating therapeutic complications. This study shows that a vital component of the pathway CRAF is directly impacted by an end product of the cascade, glutathione transferases (GST) P1 (GSTP1), driving a previously unrecognized autocrine cycle that sustains proliferation of mKRAS and mBRAF cancer cells, independent of oncogenic stimuli. The CRAF interaction with GSTP1 occurs at its N-terminal regulatory domain, CR1 motif, resulting in its stabilization, enhanced dimerization, and augmented catalytic activity. Consistent with the autocrine cycle scheme, silencing GSTP1 brought about significant suppression of proliferation of mKRAS and mBRAF cells in vitro and suppressed tumorigenesis of the xenografted mKRAS tumor in vivo. GSTP1 knockout mice showed significantly impaired carcinogenesis of mKRAS colon cancer. Consequently, hindering the autocrine loop by targeting CRAF/GSTP1 interactions should provide innovative therapeutic modalities for these cancers.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 32 Pg. 19435-19445 (08 11 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 32719131 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 the Author(s). Published by PNAS.

Chemical References

• KRAS protein, human
• GSTP1 protein, human
• Glutathione S-Transferase pi
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins c-raf
• Raf1 protein, human
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Carcinogenesis
• Cell Line, Tumor
• Cell Proliferation
• Glutathione S-Transferase pi (antagonists & inhibitors, deficiency, genetics, metabolism)
• Humans
• Mice
• Mice, Knockout
• Mutation
• Neoplasms (genetics, metabolism, pathology)
• Protein Binding
• Protein Interaction Domains and Motifs (genetics)
• Protein Multimerization
• Protein Stability
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics)
• Proto-Oncogene Proteins c-raf (chemistry, genetics, metabolism)
• Proto-Oncogene Proteins p21(ras) (antagonists & inhibitors, genetics)
• Signal Transduction