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PMID: 25056111 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Reprogramming ovarian and breast cancer cells into non-cancerous cells by low-dose metformin or SN-38 through FOXO3 activation.

Scientific reports ·Vol. 4 ·2014-07-24 ·Pages 5810

Hu T, Chung YM, Guan M, Ma M, Ma J, Berek JS, Hu MC

Abstract

Cancer is a leading cause of death worldwide. Because the cytotoxic effects of conventional chemotherapies often harm normal tissue cells along with cancer cells, conventional chemotherapies cause many unwanted or intolerable side effects. Thus, there is an unmet medical need to establish a paradigm of chemotherapy-induced differentiation of cancer cells with tolerable side effects. Here we show that low-dose metformin or SN-38 inhibits cell growth or survival in ovarian and breast cancer cells and suppresses their tumor growth in vivo. Low-dose metformin or SN-38 increases FOXO3 nuclear localization as well as the amount of DNA damage markers and downregulates the expression of a cancer-stemness marker CD44 and other stemness markers, including Nanog, Oct-4, and c-Myc, in these cancer cells. This treatment also inhibits spheroid body-formation in 3-dimensional culture. In contrast, silencing FOXO3 diminishes all these cellular events when ovarian/breast cancer cells are treated with the mentioned drugs. These results suggest that low-dose metformin or SN-38 may reprogram these cancer cells into non-cancerous cells in a FOXO3-dependent manner, and may allow patients to overcome these cancers with minimal side effects.

MeSH Terms
Active Transport, Cell Nucleus Animals Antineoplastic Agents, Phytogenic/pharmacology Breast Neoplasms/drug therapy,metabolism,pathology Camptothecin/analogs & derivatives,pharmacology Cell Line, Tumor Cell Proliferation/drug effects Cell Survival/drug effects DNA Damage Female Forkhead Box Protein O3 Forkhead Transcription Factors/physiology Gene Expression Regulation, Neoplastic/drug effects Gene Knockdown Techniques Histones/metabolism Irinotecan Metformin/pharmacology Mice, Nude Neoplastic Stem Cells/drug effects,physiology Ovarian Neoplasms/drug therapy,metabolism,pathology Phosphorylation Protein Processing, Post-Translational Tumor Burden/drug effects Xenograft Model Antitumor Assays
Chemicals
Antineoplastic Agents, Phytogenic FOXO3 protein, human Forkhead Box Protein O3 Forkhead Transcription Factors H2AX protein, human Histones Irinotecan Metformin Camptothecin
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Hu Theodore
1] Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA [2].
Chung Young Min
1] Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA [2].
Guan Michelle
Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Ma Michael
Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Ma Jessica
Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Berek Jonathan S
Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Hu Mickey C-T
Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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Article Info
Journal
Scientific reports
Abbr.
Sci Rep
ISSN
2045-2322
DOI
10.1038/srep05810
Published
2014-07-24
Epub
2014-00-24
Pages
5810
Language
English
Region
England
NLM ID
101563288
PMCID
PMC4108946
Subset
IM
Grants
NCI NIH HHS · R01 CA113859 · United States
External Links
PubMed source DOI: 10.1038/srep05810 PMC Full Text View journal details
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