H-RAS V12-induced radioresistance in HCT116 colon carcinoma cells is heregulin dependent

Rubén W. Carón, Adly Yacoub, Xiaoyu Zhu, Clint Mitchell, Song Iy Han, Takehiko Sasazuki, Senji Shirasawa, Michael P. Hagan, Steven Grant, Paul Dent

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23 Citations (Scopus)

Abstract

The abilities of mutated active K-RAS and H-RAS proteins, in an isogenic human carcinoma cell system, to modulate the activity of signaling pathways following exposure to ionizing radiation is unknown. Loss of K-RAS D13 expression in HCT116 colorectal carcinoma cells blunted basal extracellular signal-regulated kinase 1/2 (ERK1/2), AKT, and c-Jun NH2-terminal kinase 1/2 activity. Deletion of the allele to express K-RAS D13 also enhanced expression of ERBB1, ERBB3, and heregulin but nearly abolished radiation-induced activation of all signaling pathways. Expression of H-RAS V12 in HCT116 cells lacking an activated RAS molecule (H-RAS V12 cells) restored basal ERK1/2 and AKT activity to that observed in parental cells but did not restore or alter basal c-jun NH2-kinase 1/2 activity. In parental cells, radiation caused stronger ERK1/2 pathway activation compared with that of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which correlated with constitutive translocation of Raf-1 into the plasma membrane of parental cells. Inhibition of mitogen-activated protein kinase/ERK1/2, but not PI3K, radiosensitized parental cells. In H-RAS V12 cells, radiation caused stronger PI3K/AKT pathway activation compared with that of the ERK1/2 pathway, which correlated with H-RAS V12-dependent translocation of PI3K into the plasma membrane. Inhibition of PI3K, but not mitogen-activated protein kinase/ERK1/2, radiosensitized H-RAS V12 cells. Radiation-induced activation of the PI3K/AKT pathway in H-RAS V12 cells 2 to 24 hours after exposure was dependent on heregulin-stimulated ERBB3 association with membrane-localized PI3K. Neutralization of heregulin function abolished radiation-induced AKT activation and reverted the radiosensitivity of H-RAS V12 cells to those levels found in cells lacking expression of any active RAS protein. These findings show that H-RAS V12 and K-RAS D13 differentially regulate radiation-induced signaling pathway function. In HCT116 cells expressing H-RAS V12, PI3K-dependent radioresistance is mediated by both H-RAS-dependent translocation of PI3K into the plasma membrane and heregulin-induced activation of membrane-localized PI3K via ERBB3.

Original languageEnglish
Pages (from-to)243-255
Number of pages13
JournalMolecular cancer therapeutics
Volume4
Issue number2
Publication statusPublished - Feb 2005

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Carón, R. W., Yacoub, A., Zhu, X., Mitchell, C., Han, S. I., Sasazuki, T., Shirasawa, S., Hagan, M. P., Grant, S., & Dent, P. (2005). H-RAS V12-induced radioresistance in HCT116 colon carcinoma cells is heregulin dependent. Molecular cancer therapeutics, 4(2), 243-255.