Perspectives on c-Myc, Cyclin D1, and their interaction in cancer formation, progression, and response to chemotherapy.

Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, USA.
Critical reviews in oncogenesis 12/2007; 13(2):93-158. DOI: 10.1615/CritRevOncog.v13.i2.10
Source: PubMed

ABSTRACT C-myc is an oncogene that functions both in the stimulation of cell proliferation and in and apoptosis. C-myc elicits its oncogenic activity by causing immortalization, and to a lesser extent the transformation of cells, in addition to several other mechanisms. C-myc may also enhance or reduce the sensitivity of cancer cells to chemotherapy, but how this dual function is controlled is largely unclear. Cyclin D1 (D1) is another oncogene that drives cell cycle progression; it acts as a growth factor sensor to integrate extracellular signals with the cell cycle machinery, though it may also promote apoptosis. C-Myc collaborates with TGFalpha, epidermal growth factor receptor, Ras, PI3K/Akt, and NF-kappaB. in part via coordination in regulation of D1 expression, because D1 is a common downstream effector of these growth pathways. Coordination of c-Myc with D1 or its upstream activators not only accelerates tumor formation, but also may drive tumor progression to a more aggressive phenotype. Because c-Myc may effect immortalization while D1 or its upstream activators elicit transformation, targeting c-myc and D1 may be a good strategy for cancer prevention. Moreover, since D1 imposes chemoresistance on cancer cells, targeting D1 may also be a good strategy for cancer chemotherapy, whereas practicioners should be cautious to downregulate c-myc for chemotherapy, since c-Myc may elicit apoptosis.

Download full-text


Available from: Joshua Liao, Aug 06, 2014
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Colon cancer is the second leading cause of cancer related deaths in the US. Cancer stem cells have the ability to drive continued expansion of the population of malignant cells. Therefore, strategies that target cancer stem cells could be effective against colon cancer and in reducing the risk of relapse and metastasis. In this study, we evaluated the anti-proliferative and pro-apoptotic effects of triphala, a widely used formulation in Indian traditional medicine, on HCT116 coloncancer cells and human colon cancer stem cells (HCCSC). The total phenolic content, antioxidant activity, and phytochemical composition (LC-MS-MS) of the methanol extract of triphala (MET) were also measured. We observed that MET contains a variety of phenolics including naringin, quercetin, homoorientin, isorhamnetin, and hypaconitine. MET suppressed proliferation independent of p53 status in human colon cancer HCT116 cells and in HCCSCs. MET also induced p53-independent apoptosis in HCCSCs as indicated by elevated levels of cleaved PARP. Western blotting data suggested that MET suppressed protein levels of c-Myc and cyclin D1, key proteins involved in proliferation and induced apoptosis through elevation of Bax/Bcl-2 ratio. Furthermore, MET inhibited HCCSCs colony formation, a measure of self- renewal ability of cancer stem cells. Anti-cancer effects of triphala observed in our study against HCCSC warrant future studies to determine its efficacy in vivo.
    BioMed Research International 05/2015; · 2.71 Impact Factor
  • Source
    Targeting New Pathways and Cell Death in Breast Cancer, 02/2012; , ISBN: 978-953-51-0145-1
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mantle cell lymphoma (MCL) is characterized by the uncontrolled overexpression of cyclin D1. Styryl sulfonyl compounds have shown potent antitumor activity against MCL by inducing cell-cycle arrest and apoptosis. However, the exact molecular mechanism by which these compounds function is yet to be elucidated. Here, we show that the prototypical styryl sulfonyl compound ON 01910.Na decreased cyclin D1 and c-Myc protein levels in MCL cells, whereas mRNA levels of cyclin D1 were minimally affected. Notably, ON 01910.Na suppressed eukaryotic translation initiation factor 4E (eIF4E)-mediated cyclin D1 mRNA translation, decreased levels of phosphorylated Akt, mammalian target of Rapamycin (mTOR) and eIF4E-binding protein (eIF4E-BP), lowered the cap site binding activity of eIF4E and directly inhibited activity of phosphatidylinositol-3 kinase (PI-3K). Analysis of apoptotic signaling pathways revealed that ON 01910.Na induced the release of cytochrome c from mitochondria, altered expression of Bcl-2 family of proteins and stimulated activation of caspases. Taken together, styryl sulfonyls can cause a rapid decrease of cyclin D1 by blocking cyclin D1 mRNA translation through inhibition of the PI-3K/Akt/mTOR/eIF4E-BP signaling pathway and triggering a cytochrome c-dependent apoptotic pathway in MCL cells.
    Oncogene 03/2009; 28(12):1518-28. DOI:10.1038/onc.2008.502 · 8.56 Impact Factor