Evidence that RASSF1C stimulation of lung cancer cell proliferation depends on IGFBP-5 and PIWIL1 expression levels

Mark E Reeves; Matthew Firek; Shin-Tai Chen; Yousef G Amaar

doi:10.1371/journal.pone.0101679

Evidence that RASSF1C stimulation of lung cancer cell proliferation depends on IGFBP-5 and PIWIL1 expression levels

PLoS One. 2014 Jul 9;9(7):e101679. doi: 10.1371/journal.pone.0101679. eCollection 2014.

Authors

Mark E Reeves¹, Matthew Firek², Shin-Tai Chen³, Yousef G Amaar¹

Affiliations

¹ Surgical Oncology Laboratory, Loma Linda VA Medical Center, Loma Linda, California, United States of America; Department of Surgery, Loma Linda University School of Medicine, Loma Linda, California, United States of America.
² Surgical Oncology Laboratory, Loma Linda VA Medical Center, Loma Linda, California, United States of America.
³ Musculoskeletal Disease Center, Loma Linda VA Medical Center, Loma Linda, California, United States of America.

Abstract

RASSF1C is a major isoform of the RASSF1 gene, and is emerging as an oncogene. This is in contradistinction to the RASSF1A isoform, which is an established tumor suppressor. We have previously shown that RASSF1C promotes lung cancer cell proliferation and have identified RASSF1C target genes with growth promoting functions. Here, we further report that RASSF1C promotes lung cancer cell migration and enhances lung cancer cell tumor sphere formation. We also show that RASSF1C over-expression reduces the inhibitory effects of the anti-cancer agent, betulinic acid (BA), on lung cancer cell proliferation. In previous work, we demonstrated that RASSF1C up-regulates piwil1 gene expression, which is a stem cell self-renewal gene that is over-expressed in several human cancers, including lung cancer. Here, we report on the effects of BA on piwil1 gene expression. Cells treated with BA show decreased piwil1 expression. Also, interaction of IGFBP-5 with RASSF1C appears to prevent RASSF1C from up-regulating PIWIL1 protein levels. These findings suggest that IGFBP-5 may be a negative modulator of RASSF1C/ PIWIL1 growth-promoting activities. In addition, we found that inhibition of the ATM-AMPK pathway up-regulates RASSF1C gene expression.

Publication types

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

MeSH terms

Antineoplastic Agents / pharmacology
Argonaute Proteins / genetics
Argonaute Proteins / metabolism*
Betulinic Acid
Cell Movement
Cell Proliferation
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Gene Expression*
Humans
Hydroxamic Acids / pharmacology
Insulin-Like Growth Factor Binding Protein 5 / genetics
Insulin-Like Growth Factor Binding Protein 5 / metabolism*
Lung Neoplasms
Pentacyclic Triterpenes
Pyrazoles / pharmacology
Pyrimidines / pharmacology
Signal Transduction
Spheroids, Cellular
Triterpenes / pharmacology
Tumor Suppressor Proteins / genetics*
Tumor Suppressor Proteins / metabolism
beta Catenin / genetics
beta Catenin / metabolism

Substances

Antineoplastic Agents
Argonaute Proteins
CTNNB1 protein, human
Hydroxamic Acids
Insulin-Like Growth Factor Binding Protein 5
PIWIL1 protein, human
Pentacyclic Triterpenes
Pyrazoles
Pyrimidines
RASSF1 protein, human
Triterpenes
Tumor Suppressor Proteins
beta Catenin
dorsomorphin
trichostatin A
Betulinic Acid

Grants and funding

The work is funded by Loma Linda Cancer Center. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.