The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer

Nat Commun. 2022 Jul 8;13(1):3971. doi: 10.1038/s41467-022-31663-z.

Abstract

Therapeutic targeting of KRAS-mutant colorectal cancer (CRC) is an unmet need. Here, we show that Proprotein Convertase Subtilisin/Kexin type 9 (PSCK9) promotes APC/KRAS-mutant CRC and is a therapeutic target. Using CRC patient cohorts, isogenic cell lines and transgenic mice, we identify that de novo cholesterol biosynthesis is induced in APC/KRAS mutant CRC, accompanied by increased geranylgeranyl diphosphate (GGPP)─a metabolite necessary for KRAS activation. PCSK9 is the top up-regulated cholesterol-related gene. PCSK9 depletion represses APC/KRAS-mutant CRC cell growth in vitro and in vivo, whereas PCSK9 overexpression induces oncogenesis. Mechanistically, PCSK9 reduces cholesterol uptake but induces cholesterol de novo biosynthesis and GGPP accumulation. GGPP is a pivotal metabolite downstream of PCSK9 by activating KRAS/MEK/ERK signaling. PCSK9 inhibitors suppress growth of APC/KRAS-mutant CRC cells, organoids and xenografts, especially in combination with simvastatin. PCSK9 overexpression predicts poor survival of APC/KRAS-mutant CRC patients. Together, cholesterol homeostasis regulator PCSK9 promotes APC/KRAS-mutant CRC via GGPP-KRAS/MEK/ERK axis and is a therapeutic target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics
  • Animals
  • Cholesterol
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / genetics
  • Humans
  • Mice
  • Mitogen-Activated Protein Kinase Kinases
  • Proprotein Convertase 9* / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics

Substances

  • APC protein, human
  • Adenomatous Polyposis Coli Protein
  • KRAS protein, human
  • Cholesterol
  • Mitogen-Activated Protein Kinase Kinases
  • PCSK9 protein, human
  • Pcsk9 protein, mouse
  • Proprotein Convertase 9
  • Proto-Oncogene Proteins p21(ras)