Oncogenic K-Ras Signals through Epidermal Growth Factor Receptor and Wild-Type H-Ras to Promote Radiation Survival in Pancreatic and Colorectal Carcinoma Cells

Abstract

Pancreatic and colorectal carcinomas frequently express oncogenic/mutant K-Ras that contributes to both tumorigenesis and clinically observed resistance to radiation treatment. We have previously shown that farnesyltransferase inhibitors (FTI) radiosensitize many pancreatic and colorectal cancer cell lines that express oncogenic K-ras at doses that inhibit the prenylation and activation of H-Ras but not K-Ras. In the present study, we have examined the mechanism of FTI-mediated radiosensitization in cell lines that express oncogenic K-Ras and found that wild-type H-Ras is a contributor to radiation survival in tumor cells that express oncogenic K-Ras. In these experiments, inhibiting the expression of oncogenic K-Ras, wild-type H-Ras, or epidermal growth factor receptor (EGFR) led to similar levels of radiosensitization as treatment with the FTI tipifarnib. Treatment with the EGFR inhibitor gefitinib led to similar levels of radiosensitization, and the combinations of tipifarnib or gefitinib plus inhibition of K-Ras, H-Ras, or EGFR expression did not provide additional radiosensitization compared with tipifarnib or gefitinib alone. Finally, supplementing culture medium with the EGFR ligand transforming growth factor alpha was able to reverse the radiosensitizing effect of inhibiting K-ras expression. Taken together, these findings suggest that EGFR-activated H-Ras signaling is initiated by oncogenic K-Ras to promote radiation survival in pancreatic and colorectal cancers.

Stimulated PI3K-AKT Signaling Mediated through Ligand or Radiation-Induced EGFR Depends Indirectly, but not Directly, on Constitutive K-Ras Activity

“…Yet, as the amount of basal p-AKT reduction does not follow the efficient downregulation of K-Ras protein by siRNA, a function of H-Ras and/or N-Ras in stimulating AKT phosphorylation directly through interaction with PI3K, as it was proposed earlier (33,34,45), cannot be ruled out at present. Furthermore, recently, in line with our data, it was shown that K-RAS mutation in human pancreatic and colorectal cancer cells activates EGFR and H-Ras via an autocrine production of EGFR ligands, which in turn enhances postirradiation survival (64). From the data published by Cengel et al (64) and our data presented herein, it can be postulated that a compensatory effect may exist, which, via EGFR-dependent H-Ras activity, can enhance basal level of p-AKT independent of a direct interaction with K-Ras protein.…”

“…Furthermore, recently, in line with our data, it was shown that K-RAS mutation in human pancreatic and colorectal cancer cells activates EGFR and H-Ras via an autocrine production of EGFR ligands, which in turn enhances postirradiation survival (64). From the data published by Cengel et al (64) and our data presented herein, it can be postulated that a compensatory effect may exist, which, via EGFR-dependent H-Ras activity, can enhance basal level of p-AKT independent of a direct interaction with K-Ras protein.…”

Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma

“…The possible mechanisms by which this pathway regulates NPC proliferation include mutations in PI3K, PTEN deleted from chromosome 10 (PTEN), and Ras oncogene, as well as EGFR amplification (6)(7)(8). Previous studies showed that PI3K/Akt/mTOR signaling is frequently activated in many cancers, including lung, gastric, renal, and ovarian cancers (9)(10)(11)(12), and inhibition of this pathway could increase radiosensitivity (8,(13)(14)(15)(16)(17)(18). NPC cell lines and tissues also overexpressed phosphorylated Akt (p-Akt; refs.…”

KRAS, BRAF and PIK3CA mutations in human colorectal cancer: Relationship with metastatic colorectal cancer

“…Many abnormal gene expressions and dysregulated signaling pathways play important roles in tumorigenesis and tumor progression of crc (1)(2)(3)(4). egFr is a transmembrane tyrosine kinase receptor that, on ligand binding, triggers two main signaling pathways.…”

“…egFr is a transmembrane tyrosine kinase receptor that, on ligand binding, triggers two main signaling pathways. these include the rAs-rAF-MApK axis, which is mainly involved in cell proliferation, and the pI3K-pten-AKt pathway, which is mainly involved in cell survival and motility (2,5). Mutation in KrAs, BrAF or pIK3cA results in continuous activation of the downstream rAs-MApK or pI3K pathways, regardless of whether the egFr is activated (6,7).…”