Knockdown of Ron kinase inhibits mutant phosphatidylinositol 3-kinase and reduces metastasis in human colon carcinoma

Wang Jing, Ashwani Rajput, Julie L C Kan, Rebecca Rose, Liu Xiao-Qiong, Karen Kuropatwinski, Jennie Hauser, Alexander Beko, Ivan Dominiquez, Elizabeth A. Sharatt, Lisa Brattain, Charles LeVea, Feng Lei Sun, David M. Keane, Neil W. Gibson, Michael G. Brattain

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Abnormal accumulation and activation of receptor tyrosine kinase Ron (recepteur d'origine nantais) has been demonstrated in a variety of primary human cancers. We show that RNA interference-mediated knockdown of Ron kinase in a highly tumorigenic colon cancer cell line led to reduced proliferation as compared with the control cells. Decreased Ron expression sensitized HCT116 cells to growth factor deprivation stress-induced apoptosis as reflected by increased DNA fragmentation and caspase 3 activation. In addition, cell motility was decreased in Ron knockdown cells as measured by wound healing assays and transwell assays. HCT116 cells are heterozygous for gain of function mutant PIK3CA H1047R. Analysis of signaling proteins that are affected by Ron knockdown revealed that phosphatidylinositol 3-kinase (PI3K) activity of the mutant PI3K as well as AKT phosphorylation was substantially reduced in the Ron knockdown cells compared with the control cells. Moreover, we demonstrated in vivo that knockdown of Ron expression significantly reduced lung metastasis as compared with the control cells in the orthotopic models. In summary, our results demonstrate that Ron plays an essential role in maintaining malignant phenotypes of colon cancer cells through regulating mutant PI3K activity. Therefore, targeting Ron kinase could be a potential strategy for colon cancer treatment, especially in patients bearing gain of function mutant PI3K activity.

Original languageEnglish (US)
Pages (from-to)10912-10922
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number16
DOIs
StatePublished - Apr 17 2009

Fingerprint

Phosphatidylinositol 3-Kinase
Colon
Phosphotransferases
Neoplasm Metastasis
Carcinoma
Colonic Neoplasms
HCT116 Cells
Assays
Bearings (structural)
Chemical activation
Cells
RON protein
Phosphorylation
Oncology
Receptor Protein-Tyrosine Kinases
DNA Fragmentation
RNA Interference
Caspase 3
Wound Healing
Cell Movement

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Jing, W., Rajput, A., Kan, J. L. C., Rose, R., Xiao-Qiong, L., Kuropatwinski, K., ... Brattain, M. G. (2009). Knockdown of Ron kinase inhibits mutant phosphatidylinositol 3-kinase and reduces metastasis in human colon carcinoma. Journal of Biological Chemistry, 284(16), 10912-10922. https://doi.org/10.1074/jbc.M809551200

Knockdown of Ron kinase inhibits mutant phosphatidylinositol 3-kinase and reduces metastasis in human colon carcinoma. / Jing, Wang; Rajput, Ashwani; Kan, Julie L C; Rose, Rebecca; Xiao-Qiong, Liu; Kuropatwinski, Karen; Hauser, Jennie; Beko, Alexander; Dominiquez, Ivan; Sharatt, Elizabeth A.; Brattain, Lisa; LeVea, Charles; Sun, Feng Lei; Keane, David M.; Gibson, Neil W.; Brattain, Michael G.

In: Journal of Biological Chemistry, Vol. 284, No. 16, 17.04.2009, p. 10912-10922.

Research output: Contribution to journalArticle

Jing, W, Rajput, A, Kan, JLC, Rose, R, Xiao-Qiong, L, Kuropatwinski, K, Hauser, J, Beko, A, Dominiquez, I, Sharatt, EA, Brattain, L, LeVea, C, Sun, FL, Keane, DM, Gibson, NW & Brattain, MG 2009, 'Knockdown of Ron kinase inhibits mutant phosphatidylinositol 3-kinase and reduces metastasis in human colon carcinoma', Journal of Biological Chemistry, vol. 284, no. 16, pp. 10912-10922. https://doi.org/10.1074/jbc.M809551200
Jing, Wang ; Rajput, Ashwani ; Kan, Julie L C ; Rose, Rebecca ; Xiao-Qiong, Liu ; Kuropatwinski, Karen ; Hauser, Jennie ; Beko, Alexander ; Dominiquez, Ivan ; Sharatt, Elizabeth A. ; Brattain, Lisa ; LeVea, Charles ; Sun, Feng Lei ; Keane, David M. ; Gibson, Neil W. ; Brattain, Michael G. / Knockdown of Ron kinase inhibits mutant phosphatidylinositol 3-kinase and reduces metastasis in human colon carcinoma. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 16. pp. 10912-10922.
@article{e716aa934d404999a977f6d8985304b9,
title = "Knockdown of Ron kinase inhibits mutant phosphatidylinositol 3-kinase and reduces metastasis in human colon carcinoma",
abstract = "Abnormal accumulation and activation of receptor tyrosine kinase Ron (recepteur d'origine nantais) has been demonstrated in a variety of primary human cancers. We show that RNA interference-mediated knockdown of Ron kinase in a highly tumorigenic colon cancer cell line led to reduced proliferation as compared with the control cells. Decreased Ron expression sensitized HCT116 cells to growth factor deprivation stress-induced apoptosis as reflected by increased DNA fragmentation and caspase 3 activation. In addition, cell motility was decreased in Ron knockdown cells as measured by wound healing assays and transwell assays. HCT116 cells are heterozygous for gain of function mutant PIK3CA H1047R. Analysis of signaling proteins that are affected by Ron knockdown revealed that phosphatidylinositol 3-kinase (PI3K) activity of the mutant PI3K as well as AKT phosphorylation was substantially reduced in the Ron knockdown cells compared with the control cells. Moreover, we demonstrated in vivo that knockdown of Ron expression significantly reduced lung metastasis as compared with the control cells in the orthotopic models. In summary, our results demonstrate that Ron plays an essential role in maintaining malignant phenotypes of colon cancer cells through regulating mutant PI3K activity. Therefore, targeting Ron kinase could be a potential strategy for colon cancer treatment, especially in patients bearing gain of function mutant PI3K activity.",
author = "Wang Jing and Ashwani Rajput and Kan, {Julie L C} and Rebecca Rose and Liu Xiao-Qiong and Karen Kuropatwinski and Jennie Hauser and Alexander Beko and Ivan Dominiquez and Sharatt, {Elizabeth A.} and Lisa Brattain and Charles LeVea and Sun, {Feng Lei} and Keane, {David M.} and Gibson, {Neil W.} and Brattain, {Michael G.}",
year = "2009",
month = "4",
day = "17",
doi = "10.1074/jbc.M809551200",
language = "English (US)",
volume = "284",
pages = "10912--10922",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "16",

}

TY - JOUR

T1 - Knockdown of Ron kinase inhibits mutant phosphatidylinositol 3-kinase and reduces metastasis in human colon carcinoma

AU - Jing, Wang

AU - Rajput, Ashwani

AU - Kan, Julie L C

AU - Rose, Rebecca

AU - Xiao-Qiong, Liu

AU - Kuropatwinski, Karen

AU - Hauser, Jennie

AU - Beko, Alexander

AU - Dominiquez, Ivan

AU - Sharatt, Elizabeth A.

AU - Brattain, Lisa

AU - LeVea, Charles

AU - Sun, Feng Lei

AU - Keane, David M.

AU - Gibson, Neil W.

AU - Brattain, Michael G.

PY - 2009/4/17

Y1 - 2009/4/17

N2 - Abnormal accumulation and activation of receptor tyrosine kinase Ron (recepteur d'origine nantais) has been demonstrated in a variety of primary human cancers. We show that RNA interference-mediated knockdown of Ron kinase in a highly tumorigenic colon cancer cell line led to reduced proliferation as compared with the control cells. Decreased Ron expression sensitized HCT116 cells to growth factor deprivation stress-induced apoptosis as reflected by increased DNA fragmentation and caspase 3 activation. In addition, cell motility was decreased in Ron knockdown cells as measured by wound healing assays and transwell assays. HCT116 cells are heterozygous for gain of function mutant PIK3CA H1047R. Analysis of signaling proteins that are affected by Ron knockdown revealed that phosphatidylinositol 3-kinase (PI3K) activity of the mutant PI3K as well as AKT phosphorylation was substantially reduced in the Ron knockdown cells compared with the control cells. Moreover, we demonstrated in vivo that knockdown of Ron expression significantly reduced lung metastasis as compared with the control cells in the orthotopic models. In summary, our results demonstrate that Ron plays an essential role in maintaining malignant phenotypes of colon cancer cells through regulating mutant PI3K activity. Therefore, targeting Ron kinase could be a potential strategy for colon cancer treatment, especially in patients bearing gain of function mutant PI3K activity.

AB - Abnormal accumulation and activation of receptor tyrosine kinase Ron (recepteur d'origine nantais) has been demonstrated in a variety of primary human cancers. We show that RNA interference-mediated knockdown of Ron kinase in a highly tumorigenic colon cancer cell line led to reduced proliferation as compared with the control cells. Decreased Ron expression sensitized HCT116 cells to growth factor deprivation stress-induced apoptosis as reflected by increased DNA fragmentation and caspase 3 activation. In addition, cell motility was decreased in Ron knockdown cells as measured by wound healing assays and transwell assays. HCT116 cells are heterozygous for gain of function mutant PIK3CA H1047R. Analysis of signaling proteins that are affected by Ron knockdown revealed that phosphatidylinositol 3-kinase (PI3K) activity of the mutant PI3K as well as AKT phosphorylation was substantially reduced in the Ron knockdown cells compared with the control cells. Moreover, we demonstrated in vivo that knockdown of Ron expression significantly reduced lung metastasis as compared with the control cells in the orthotopic models. In summary, our results demonstrate that Ron plays an essential role in maintaining malignant phenotypes of colon cancer cells through regulating mutant PI3K activity. Therefore, targeting Ron kinase could be a potential strategy for colon cancer treatment, especially in patients bearing gain of function mutant PI3K activity.

UR - http://www.scopus.com/inward/record.url?scp=67449098154&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67449098154&partnerID=8YFLogxK

U2 - 10.1074/jbc.M809551200

DO - 10.1074/jbc.M809551200

M3 - Article

VL - 284

SP - 10912

EP - 10922

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 16

ER -