Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression

Abstract

RAS is the most frequently mutated oncogene in human cancers. Despite decades of effort, anti-RAS therapies have remained elusive. Isoprenylcysteine carboxylmethyltransferase (ICMT) methylates RAS and other CaaX-containing proteins, but its potential as a target for cancer therapy has not been fully evaluated. We crossed a Pdx1-Cre;LSL-Kras G12D mouse, which is a model of pancreatic ductal adenocarcinoma (PDA), with a mouse harboring a floxed allele of Icmt. Surprisingly, we found that ICMT deficiency dramatically accelerated the development and progression of neoplasia. ICMT-deficient pancreatic ductal epithelial cells had a slight growth advantage and were resistant to premature senescence by a mechanism that involved suppression of cyclin-dependent kinase inhibitor 2A (p16 INK4A ) expression. ICMT deficiency precisely phenocopied Notch1 deficiency in the Pdx1-Cre;LSL-Kras G12D model by exacerbating pancreatic intraepithelial neoplasias, promoting facial papillomas, and derepressing Wnt signaling. Silencing ICMT in human osteosarcoma cells decreased Notch1 signaling in response to stimulation with cell-surface ligands. Additionally, targeted silencing of Ste14, the Drosophila homolog of Icmt, resulted in defects in wing development, consistent with Notch loss of function. Our data suggest that ICMT behaves like a tumor suppressor in PDA because it is required for Notch1 signaling.Introduction RAS is the most frequently mutated oncogene in human cancer (1). This has made RAS the target of drug discovery efforts for more than three decades, but effective anti-RAS therapies have remained elusive (2). RAS is a prototypical small GTPase that functions as a binary molecular switch to regulate a number of signaling pathways including those that control growth and differentiation. RAS is inactive when GDP bound and is active when it binds GTP. The GDP/GTP cycle is controlled by guanine nucleotide exchange factors (GEFs) that activate RAS and by GTPase-activating proteins (GAPs) that dramatically accelerate the rate of GTP hydrolysis catalyzed by RAS, thereby limiting RAS activity (3). The oncogenic mutations found in human cancer are one of several single nucleotide changes in codons 12, 13, or 61 that render RAS insensitive to GAPs and reduce the intrinsic rate of GTP hydrolysis, thus allowing the accumulation of GTP-bound, activated RAS (1, 4). Attempts to devise therapeutic agents that reverse the accumulation of GTP-bound RAS have failed. Accordingly, investigators have taken an alternate approach driven by another hallmark of RAS biology: its regulation of signaling pathways only when associated with cellular membranes (5).RAS is a peripheral membrane protein that gains affinity for membranes as a consequence of a series of posttranslational modifications of a C-terminal CaaX motif (6). The CaaX sequence is first modified by farnesyltransferase (FTase), which adds a farnesyl lipid to the cysteine. Next, RAS-converting enzyme 1 (RCE1) removes the aaX amino acids. Finally, isoprenylcysteine carboxylmethyltransferas...

Identifications of genetic differences between metastatic and non-metastatic osteosarcoma samples based on bioinformatics analysis

“…So, we inferred that OS pathogenesis may be related to wnt and Myc pathway abnormality and the genes in these functional nodes, such This result agreed with the findings of previous studies: TGFB1 involves in the osteoblastic changes in bone metastasis [19], and the differentiation of cancer cells to cancer stem cells in OS [20]; FLT3 could inhibit proliferation and promote cell death in OS cell lines [21]. Moreover, the metastatic and non-metastatic OS are closely related to KDM1A gene down-regulation, which is an evidence supporting the points that KDM1A is a therapeutic target for OS [22] and KRAS is a underlying target gene for OS treatment [23].…”

Divergent Roles of CAAX Motif-signaled Posttranslational Modifications in the Regulation and Subcellular Localization of Ral GTPases

“…In a mouse model of K-Ras-induced myeloproliferative disease, loss of ICMT ameliorated tumor growth, whereas loss of RCE1 accelerated it (50,51). More recently, it was found that ICMT deficiency enhanced K-Ras-driven pancreatic cancer development (52). A logical explanation for these different consequences for Ras-driven oncogenesis is that ablation of RCE1 or ICMT expression alters the function of other CAAX-terminating prenylated proteins, including small GTPases such as Ral and Rac that function downstream of Ras effector signaling, or of Ras family proteins that can act as tumor suppressors (53).…”

Lunatic Fringe is a potent tumor suppressor in Kras-initiated pancreatic cancer

“…3,6 On the other hand, deficiency of isoprenylcysteine carboxylmethyltransferase, which methylates Ras and is considered a target for cancer therapy, surprisingly exacerbated Kras-driven PDAC owing to suppression of Notch1. 7 Therefore, roles of individual Notch receptors and their regulation in PDAC remain to be defined.…”