PDP1 promotes KRAS mutant colorectal cancer progression by serving as a scaffold for BRAF and MEK1.

Publisher: Elsevier Science Ireland Country of Publication: Ireland NLM ID: 7600053 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7980 (Electronic) Linking ISSN: 03043835 NLM ISO Abbreviation: Cancer Lett Subsets: MEDLINE

Publication: Limerick : Elsevier Science Ireland
Original Publication: Amsterdam, Elsevier/North-Holland.

Colorectal Neoplasms*/genetics ; Colorectal Neoplasms*/pathology ; Colorectal Neoplasms*/drug therapy ; Colorectal Neoplasms*/metabolism ; Disease Progression* ; MAP Kinase Kinase 1*/genetics ; MAP Kinase Kinase 1*/metabolism ; MAP Kinase Kinase 1*/antagonists & inhibitors ; Proto-Oncogene Proteins B-raf*/genetics ; Proto-Oncogene Proteins B-raf*/metabolism ; Proto-Oncogene Proteins p21(ras)*/genetics ; Proto-Oncogene Proteins p21(ras)*/metabolism; Animals ; Female ; Humans ; Male ; Mice ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/metabolism ; Mice, Nude ; Mutation ; Up-Regulation

The oncogenic role of KRAS in colorectal cancer (CRC) progression is well-established. Despite this, identifying effective therapeutic targets for KRAS-mutated CRC remains a significant challenge. This study identifies pyruvate dehydrogenase phosphatase catalytic subunit 1 (PDP1) as a previously unrecognized yet crucial regulator in the progression of KRAS mutant CRC. A substantial upregulation of PDP1 expression is observed in KRAS mutant CRC cells and tissues compared to wild-type KRAS samples, which correlates with poorer prognosis. Functional experiments elucidate that PDP1 accelerates the malignance of KRAS mutant CRC cells, both in vitro and in vivo. Mechanistically, PDP1 acts as a scaffold, enhancing BRAF and MEK1 interaction and activating the MAPK signaling, thereby promoting CRC progression. Additionally, transcription factor KLF5 is identified as the key regulator for PDP1 upregulation in KRAS mutant CRC. Crucially, targeting PDP1 combined with MAPK inhibitors exhibits an obvious inhibitory effect on KRAS mutant CRC. Overall, PDP1 is underscored as a vital oncogenic driver and promising therapeutic target for KRAS mutant CRC.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Keywords: Colorectal cancer; Mutant KRAS; PDP1; Scaffold; Sotorasib

EC 2.7.11.1 (BRAF protein, human)
0 (KLF5 protein, human)
0 (KRAS protein, human)
0 (Kruppel-Like Transcription Factors)
EC 2.7.12.2 (MAP Kinase Kinase 1)
EC 2.7.12.2 (MAP2K1 protein, human)
EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
EC 3.1.3.43 (PDP1 protein, human)

Date Created: 20240607 Date Completed: 20240731 Latest Revision: 20240909

20240909

10.1016/j.canlet.2024.217007

38849010