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PMID: 21757645 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Asymmetric cancer cell division regulated by AKT.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 108 ·No. 31 ·2011-08-02 ·Pages 12845-50

Dey-Guha I, Wolfer A, Yeh AC, G Albeck J, Darp R, Leon E, Wulfkuhle J, Petricoin EF, Wittner BS, Ramaswamy S

Abstract

Human tumors often contain slowly proliferating cancer cells that resist treatment, but we do not know precisely how these cells arise. We show that rapidly proliferating cancer cells can divide asymmetrically to produce slowly proliferating "G0-like" progeny that are enriched following chemotherapy in breast cancer patients. Asymmetric cancer cell division results from asymmetric suppression of AKT/PKB kinase signaling in one daughter cell during telophase of mitosis. Moreover, inhibition of AKT signaling with small-molecule drugs can induce asymmetric cancer cell division and the production of slow proliferators. Cancer cells therefore appear to continuously flux between symmetric and asymmetric division depending on the precise state of their AKT signaling network. This model may have significant implications for understanding how tumors grow, evade treatment, and recur.

MeSH Terms
Blotting, Western Breast Neoplasms/genetics,metabolism,pathology Cell Division Cell Line, Tumor Cell Survival/drug effects Dose-Response Relationship, Drug Female Gene Expression Profiling Gene Expression Regulation, Neoplastic HCT116 Cells Heterocyclic Compounds, 3-Ring/chemistry,pharmacology Humans Luminescent Proteins/genetics,metabolism Microscopy, Confocal Models, Biological Molecular Structure Neoplasms/genetics,metabolism,pathology Oligonucleotide Array Sequence Analysis Proto-Oncogene Proteins c-akt/antagonists & inhibitors,genetics,metabolism Reactive Oxygen Species/metabolism Resting Phase, Cell Cycle Signal Transduction/drug effects Time Factors
Chemicals
Heterocyclic Compounds, 3-Ring Luminescent Proteins MK 2206 Reactive Oxygen Species Proto-Oncogene Proteins c-akt
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Dey-Guha Ipsita
Centers for Cancer Research, Regenerative Medicine, Human Genetics Research, and Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Wolfer Anita
Yeh Albert C
G Albeck John
Darp Revati
Leon Eduardo
Wulfkuhle Julia
Petricoin Emanuel F
Wittner Ben S
Ramaswamy Sridhar
References (35)
35 references, click to expand
  1. Chromatin modifications and their function.
    Cell. 2007 Feb 23;128(4):693-705 PMID: 17320507
  2. Chromatin poises miRNA- and protein-coding genes for expression.
    Genome Res. 2009 Oct;19(10):1742-51 PMID: 19713549
  3. Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell.
    Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10032-7 PMID: 10944195
  4. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations.
    Cell. 2010 Apr 2;141(1):69-80 PMID: 20371346
  5. Inhibition of phosphorylation of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to paclitaxel.
    J Biol Chem. 2002 Sep 6;277(36):33490-500 PMID: 12087097
  6. Histone hypomethylation is an indicator of epigenetic plasticity in quiescent lymphocytes.
    EMBO J. 2004 Nov 10;23(22):4462-72 PMID: 15510223
  7. Bone morphogenetic protein signaling inhibits hair follicle anagen induction by restricting epithelial stem/progenitor cell activation and expansion.
    Stem Cells. 2006 Dec;24(12):2826-39 PMID: 16960130
  8. Asymmetric and symmetric stem-cell divisions in development and cancer.
    Nature. 2006 Jun 29;441(7097):1068-74 PMID: 16810241
  9. Cell-cycle-phase progression analysis identifies unique phenotypes of major prognostic and predictive significance in breast cancer.
    Br J Cancer. 2009 Mar 24;100(6):959-70 PMID: 19240714
  10. Association of reactive oxygen species levels and radioresistance in cancer stem cells.
    Nature. 2009 Apr 9;458(7239):780-3 PMID: 19194462
  11. AKT/PKB signaling: navigating downstream.
    Cell. 2007 Jun 29;129(7):1261-74 PMID: 17604717
  12. Mst1-FoxO signaling protects Naïve T lymphocytes from cellular oxidative stress in mice.
    PLoS One. 2009 Nov 24;4(11):e8011 PMID: 19956688
  13. Coexistence of quiescent and active adult stem cells in mammals.
    Science. 2010 Jan 29;327(5965):542-5 PMID: 20110496
  14. G1 cell-cycle control and cancer.
    Nature. 2004 Nov 18;432(7015):298-306 PMID: 15549091
  15. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance.
    Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16158-63 PMID: 17911267
  16. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis.
    Cancer Cell. 2008 Dec 9;14(6):458-70 PMID: 19061837
  17. Allosteric inhibitors of Akt1 and Akt2: a naphthyridinone with efficacy in an A2780 tumor xenograft model.
    Bioorg Med Chem Lett. 2008 Jun 1;18(11):3178-82 PMID: 18479914
  18. The epithelial-mesenchymal transition generates cells with properties of stem cells.
    Cell. 2008 May 16;133(4):704-15 PMID: 18485877
  19. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo.
    Mol Cancer Ther. 2010 Jul;9(7):1956-67 PMID: 20571069
  20. A new description of cellular quiescence.
    PLoS Biol. 2006 Mar;4(3):e83 PMID: 16509772
  21. Will kinase inhibitors have a dark side?
    N Engl J Med. 2006 Jul 20;355(3):313-5 PMID: 16855275
  22. Dividing cellular asymmetry: asymmetric cell division and its implications for stem cells and cancer.
    Genes Dev. 2009 Dec 1;23(23):2675-99 PMID: 19952104
  23. Cisplatin induces PKB/Akt activation and p38(MAPK) phosphorylation of the EGF receptor.
    Oncogene. 2006 Nov 30;25(56):7381-90 PMID: 16785992
  24. Prospective identification of tumorigenic breast cancer cells.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8 PMID: 12629218
  25. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress.
    Cell. 2007 Jan 26;128(2):325-39 PMID: 17254970
  26. Reverse phase protein microarrays which capture disease progression show activation of pro-survival pathways at the cancer invasion front.
    Oncogene. 2001 Apr 12;20(16):1981-9 PMID: 11360182
  27. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells.
    Nature. 2004 Oct 21;431(7011):997-1002 PMID: 15496926
  28. Mechanisms of drug inhibition of signalling molecules.
    Nature. 2006 May 25;441(7092):457-62 PMID: 16724058
  29. Antiestrogen-resistant subclones of MCF-7 human breast cancer cells are derived from a common monoclonal drug-resistant progenitor.
    Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14536-41 PMID: 19706540
  30. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth.
    Cell. 2010 May 14;141(4):583-94 PMID: 20478252
  31. The clonal evolution of tumor cell populations.
    Science. 1976 Oct 1;194(4260):23-8 PMID: 959840
  32. Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling.
    PLoS One. 2008 Aug 26;3(8):e3065 PMID: 18725974
  33. Asymmetric cell division: recent developments and their implications for tumour biology.
    Nat Rev Mol Cell Biol. 2010 Dec;11(12):849-60 PMID: 21102610
  34. Epigenetics of human T cells during the G0-->G1 transition.
    Genome Res. 2009 Aug;19(8):1325-37 PMID: 19546172
  35. MYC regulation of a "poor-prognosis" metastatic cancer cell state.
    Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3698-703 PMID: 20133671
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1109632108
Published
2011-08-02
Epub
2011-00-14
Pages
12845-50
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC3150943
Subset
IM
Grants
NCI NIH HHS · P50 CA089393 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · P50CA127003 · United States
NCI NIH HHS · R01 CA185086 · United States
NCI NIH HHS · P50 CA89393 · United States
NCI NIH HHS · K08 CA100339 · United States
NCI NIH HHS · P50 CA127003 · United States
Databases
GEO
GSE30465
External Links
PubMed source DOI: 10.1073/pnas.1109632108 PMC Full Text View journal details
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