KRAS-mediated up-regulation of RRM2 expression is essential for the proliferation of colorectal cancer cell lines

Yasuhiro Yoshida; Toshiyuki Tsunoda; Keiko Doi; Yoko Tanaka; Takahiro Fujimoto; Takashi Machida; Takeharu Ota; Midori Koyanagi; Yasuo Takashima; Takehiko Sasazuki; Masahide Kuroki; Akinori Iwasaki; Senji Shirasawa

KRAS-mediated up-regulation of RRM2 expression is essential for the proliferation of colorectal cancer cell lines

Anticancer Res. 2011 Jul;31(7):2535-9.

Authors

Yasuhiro Yoshida¹, Toshiyuki Tsunoda, Keiko Doi, Yoko Tanaka, Takahiro Fujimoto, Takashi Machida, Takeharu Ota, Midori Koyanagi, Yasuo Takashima, Takehiko Sasazuki, Masahide Kuroki, Akinori Iwasaki, Senji Shirasawa

Affiliation

¹ Department of Cell Biology, Faculty of Medicine, Fukuoka University 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.

PMID: 21873171

Abstract

Background: We previously investigated the mRNA expression of colorectal cancer cell lines via a microarray analysis and found several genes that were significantly up-regulated by oncogenic KRAS under serum-starved conditions. Of these genes, we focused on ribonucleotide reductase M2 (RRM2), which was reported to be associated with DNA synthesis.

Materials and methods: Cell proliferation and colony formation assays were performed using HCT116 cells transfected with lentiviral RRM2-shRNAs.

Results: Under serum-starved conditions, the expression level of RRM2 protein increased in HCT116 cells compared to HKe3 cells (HCT116 cells with a disruption in oncogenic KRAS), and the re-expression of KRAS in HKe3 cells induced the expression of RRM2. Both the cell proliferation under serum-depleted conditions and the anchorage-independent growth were impaired by the reduction of RRM2 protein expression.

Conclusion: RRM2 represents a novel therapeutic target, thus highlighting the potential utility of RRM2 inhibitors in colorectal cancer with oncogenic KRAS.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / metabolism
Adenocarcinoma / pathology*
Cell Adhesion
Cell Culture Techniques
Cell Division
Cell Line, Tumor / metabolism
Colorectal Neoplasms / genetics
Colorectal Neoplasms / metabolism
Colorectal Neoplasms / pathology*
Culture Media, Serum-Free
Gene Expression Regulation, Neoplastic*
Genes, ras
Humans
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / biosynthesis
Neoplasm Proteins / genetics
Neoplasm Proteins / physiology*
Oncogene Proteins / genetics
Oncogene Proteins / physiology*
Point Mutation
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / physiology*
Proto-Oncogene Proteins p21(ras)
RNA, Small Interfering / pharmacology
Ribonucleoside Diphosphate Reductase / antagonists & inhibitors
Ribonucleoside Diphosphate Reductase / biosynthesis*
Ribonucleoside Diphosphate Reductase / genetics
Ribonucleoside Diphosphate Reductase / physiology
Tumor Stem Cell Assay
Up-Regulation
ras Proteins / genetics
ras Proteins / physiology*

Substances

Culture Media, Serum-Free
KRAS protein, human
Neoplasm Proteins
Oncogene Proteins
Proto-Oncogene Proteins
RNA, Small Interfering
ribonucleotide reductase M2
Ribonucleoside Diphosphate Reductase
Proto-Oncogene Proteins p21(ras)
ras Proteins