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Review
. 2016 Jan 28;12(3):338-46.
doi: 10.7150/ijbs.15020. eCollection 2016.

The Significance of Ras Activity in Pancreatic Cancer Initiation

Craig D Logsdon  1 , Weiqin Lu  2
Affiliations
Review

The Significance of Ras Activity in Pancreatic Cancer Initiation

Craig D Logsdon et al. Int J Biol Sci. .

Abstract

The genetic landscape of pancreatic cancer shows nearly ubiquitous mutations of K-RAS. However, oncogenic K-Ras(mt) alone is not sufficient to lead to pancreatic ductal adenocarcinoma (PDAC) in either human or in genetically modified adult mouse models. Many stimulants, such as high fat diet, CCK, LPS, PGE2 and others, have physiological effects at low concentrations that are mediated in part through modest increases in K-Ras activity. However, at high concentrations, they induce inflammation that, in the presence of oncogenic K-Ras expression, substantially accelerates PDAC formation. The mechanism involves increased activity of oncogenic K-Ras(mt). Unlike what has been proposed in the standard paradigm for the role of Ras in oncogenesis, oncogenic K-Ras(mt) is now known to not be constitutively active. Rather, it can be activated by standard mechanisms similar to wild-type K-Ras, but its activity is sustained for a prolonged period. Furthermore, if the level of K-Ras activity exceeds a threshold at which it begins to generate its own activators, then a feed-forward loop is formed between K-Ras activity and inflammation and pathological processes including oncogenesis are initiated. Oncogenic K-Ras(mt) activation, a key event in PDAC initiation and development, is subject to complex regulatory mechanisms. Reagents which inhibit inflammation, such as the Cox2 inhibitor celecoxib, block the feed-forward loop and prevent induction of PDAC in models with endogenous oncogenic K-Ras(mt). Increased understanding of the role of activating and inhibitory mechanisms on oncogenic K-Ras(mt) activity is of paramount importance for the development of preventive and therapeutic strategies to fight against this lethal disease.

Keywords: K-RAS.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Fig 1
Fig 1
Activation of Ras by GTP loading. Wild-type K-Ras is typically bound with GDP and thus inactive (“off”). Activation of guanine exchange factors (GEFs) by interactions with receptors leads to the loading of GTP in place of GDP and K-Ras changes to the active conformation (“on”). K-Ras has intrinsic GTPase activity that will convert GTP back to GDP and turn the system back to its inactive state. However, the GTPase activity of native K-Ras is low and is greatly accelerated by interactions with GTPase activating proteins (GAPs). Oncogenic mutations in K-Ras disrupt interactions with GAPs. In the standard paradigm, this leads to constitutively active K-Ras. In the revised paradigm, this leads to prolonged signaling from oncogenic K-Ras after activation by GEFs or other mechanisms.
Fig 2
Fig 2
Activation of Ras stimulates a large number of down-stream pathways. Canonical activation of Ras occurs when a tyrosine kinase receptor (e.g. EGFR) is occupied by a ligand leading to phosphorylation of the receptor and interaction with signaling components such as SHC which then binds to GRB2 and ultimately with the GEF, SOS. SOS acts on Ras to replace GDP with GTP. GTP loading changes the conformation of Ras allowing it to interact with multiple effectors. The five most widely studied effects include PI3K, PLCε, Raf, Tiam1, and Ral GEF. However, many more effectors have been described. One thing not indicated by figures of this sort is the relative sensitivities of the various effectors.
Fig 3
Fig 3
Influence of total Ras activity on cell function. While individual molecules or Ras act as binary switches, the biological response depends on the summation of active Ras molecules. Low levels of Ras stimulants activate a small proportion of available Ras molecules. Low Ras activity is involved in maintenance of cellular homeostasis and activities such as protein synthesis. Slightly elevated total Ras activity stimulates growth, both hypertrophy and hyperplasia. High levels of Ras activity generate inflammatory mediators and inflammation. Very high levels of Ras activity typically lead to cell cycle arrest and senescence. However, if senescence mechanisms are compromised, high levels of Ras activity transform the cells leading to carcinogenesis.
Figure 4
Figure 4
K-Ras-GTP loading is increased by stimulants and mutant oncogenic K-Ras prolongs the activity. Murine pancreatic acinar cells isolated from mice that express endogenous levels of oncogenic mutant K-Ras in all acinar cells, and those isolated from wild-type mice, were stimulated with a variety of stimulants (CCK, PGE2 and LPS). For each of these stimulants it was observed that Ras was activated by treating the cells (indicated by analysis of GTP binding) and that the activity of Ras was prolonged in the cells expressing oncogenic mutant K-Ras.
Figure 5
Figure 5
GPCR transactivation of EGFR leading to Ras stimulation. Stimulation of many GPCRs leads, through standard second messenger pathways, to secretion or activation of ADAMs or MMPs. Activity of these proteases frees bound EGFR ligands which interact with EGFR and generate typical tyrosine kinase signaling pathways including activation of RAS.
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