Liao DJ, Thakur A, Wu J, Biliran H, Sarkar FH.. Perspectives on c-Myc, cyclin D1, and their interaction in cancer formation, progression, and response to chemotherapy. Crit Rev Oncog 13: 93-158

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.

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Available from: Joshua Liao, Aug 06, 2014
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    • "Coordination of c-Myc with cyclin D1 or its upstream activators may not only accelerate tumor formation but also drive tumor progression to a more aggressive phenotype. Because c-Myc may affect immortalization while cyclin D1 elicits transformation, agents that target c-Myc and cyclin D1 can be good chemopreventive agents [11]. Recently, c-Myc has been recognized as an important regulator of stem cell biology as it may serve as a link connecting malignancy and " stemness " and has central role in cell proliferation, apoptosis, and survival of CSCs [12] [13] [14]. "
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    ABSTRACT: Colon cancer is the second leading cause of cancer related deaths in the USA. Cancer stem cells (CSCs) have the ability to drive continued expansion of the population of malignant cells. Therefore, strategies that target CSCs could be effective against colon cancer and in reducing the risk of relapse and metastasis. In this study, we evaluated the antiproliferative and proapoptotic effects of triphala, a widely used formulation in Indian traditional medicine, on HCT116 colon cancer cells and human colon cancer stem cells (HCCSCs). The total phenolic content, antioxidant activity, and phytochemical composition (LC-MS-MS) of methanol extract of triphala (MET) were also measured. We observed that MET contains a variety of phenolics including naringin, quercetin, homoorientin, and isorhamnetin. MET suppressed proliferation independent of p53 status in HCT116 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 CSCs self-renewal ability. Anticancer effects of triphala observed in our study warrant future studies to determine its efficacy in vivo.
    Full-text · Article · Jul 2015
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    • "Coordination of c-Myc with cyclin D1 or its upstream activators may not only accelerate tumor formation but also drive tumor progression to a more aggressive phenotype. Because c-Myc may affect immortalization while cyclin D1 elicits transformation, agents that target c-Myc and cyclin D1 can be good chemopreventive agents [11]. Recently, c-Myc has been recognized as an important regulator of stem cell biology as it may serve as a link connecting malignancy and " stemness " and has central role in cell proliferation, apoptosis, and survival of CSCs [12] [13] [14]. "
    [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.
    Full-text · Article · May 2015 · BioMed Research International
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    • "eIF4E3 competes with eIF4E1 in binding cap and acts as a tumor suppressor[21]. Multiple proteins have been demonstrated to be enhanced in breast CSCs, such as the CSC markers NANOG and OCT4[22], the metastasis regulator CXCR4[23, 24], the epithelial–mesenchymal transition (EMT)[25] regulator c-MYB[26], or the cell proliferation key factors c-MYC[27] and cyclin D1[28, 29]. "
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    ABSTRACT: Cancer death is a leading cause of global mortality. An estimated 14.1 million new cancer cases and 8.2 million cancer deaths occurred worldwide in 2012 alone. Cancer stem cells (CSCs) within tumors are essential for tumor metastasis and reoccurrence, the key factors of cancer lethality. Here we report that 4EGI-1, an inhibitor of the interaction between translation initiation factors eIF4E1 and eIF4G1 effectively inhibits breast CSCs through selectively reducing translation persistent in breast CSCs. Translation initiation factor eIF4E1 is significantly enhanced in breast CSCs in comparison to non-CSC breast cancer cells. 4EGI-1 presents increased cytotoxicity to breast CSCs compared to non-CSC breast cancer cells. 4EGI-1 promotes breast CSC differentiation and represses breast CSC induced tube-like structure formation of human umbilical vein endothelial cells (HUVECs). 4EGI-1 isomers suppress breast CSC tumorangiogenesis and tumor growth in vivo. In addition, 4EGI-1 decreases proliferation in and induces apoptosis into breast CSC tumor cells. Furthermore, 4EGI-1 selectively inhibits translation of mRNAs encoding NANOG, OCT4, CXCR4, c-MYC and VEGF in breast CSC tumors. Our study demonstrated that 4EGI-1 targets breast CSCs through selective inhibition of translation critical for breast CSCs, suggesting that selective translation initiation interference might be an avenue targeting CSCs within tumors.
    Full-text · Article · Jun 2014 · Oncotarget
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