Differentiation-promoting effect of 1-O (2 methoxy) hexadecyl glycerol in human colon cancer cells

Wang, Hongmei; Rajagopal, Sriram; Reynolds, Sharon; Cederberg, Hokan; Chakrabarty, Subhas

doi:10.1002/(sici)1097-4652(199902)178:2<173::aid-jcp6>3.0.co;2-q

Cited by 15 publications

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“…The multiple pathways associated with the loss of BRCA1 in tumor promotion are not fully understood. Key features that distinguish malignant cells from normal epithelial cells are the abilities of malignant cells to migrate, invade and grow in an anchorage‐independent manner 27, 28. The expression level of the anti‐apoptotic protein survivin is relatively high in cancer cells by comparison to normal epithelial cells, which do not usually express survivin 29, 30.…”

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BRCA1 modulates malignant cell behavior, the expression of survivin and chemosensitivity in human breast cancer cells

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Patmasiriwat

Chakrabarty

2009

Intl Journal of Cancer

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BRCA1 is a multifunctional tumor-suppressive protein. Many functional aspects of BRCA1 are not fully understood. We used a shRNA approach to probe the function of BRCA1 in human breast cancer cells. Knocking down BRCA1 expression by shRNA in the wild-type BRCA1 human breast cancer MCF-7 and MDA-MB-231 cells resulted in an increase in cell proliferation, anchorage-independent growth, cell migration, invasion and a loss of p21/Waf1 and p27 Kip1 expression. In BRCA1 knocked-down cells, the expression of survivin was significantly up regulated with a concurrent decrease in cellular sensitivity to paclitaxel. We also found that cells harboring endogenous mutant or defective BRCA1 (MDA-MB-436 and HCC1937) were highly proliferative and expressed a relatively low level of p21/Waf1 and p27 Kip1 by comparison to wild-type BRCA1 cells. Cells harboring mutated BRCA1 also expressed a high level of survivin and were relatively resistant to paclitaxel by comparison to wild-type cells. Increase resistance to paclitaxel was due to an increase in the expression of survivin in both the BRCA1 knocked-down and mutant BRCA1 cells because knocking down survivin expression by siRNA restored sensitivity to paclitaxel. We conclude that BRCA1 down-modulates the malignant behavior of breast cancer cells, promotes the expression of p21/Waf1, p27 Kip1 and inhibits the expression of survivin. Moreover, loss of BRCA1 expression or function leads to an increase in survivin expression and a reduction in chemosensitivity to paclitaxel. ' UICCKey words: BRCA1; p21/Waf1; p27Kip1; survivin; chemosensitivity Hereditary breast cancer can be caused by germline mutations in 1 of the 2 tumor suppressor genes, BRCA1 and BRCA2 resulting in a loss of gene function. 1,2 Women carrying 1 mutated BRCA1 allele are at increased risk of developing breast cancer but tumor initiation requires a loss of the wild-type allele indicating that BRCA1 is a tumor suppressor gene. 3,4 Hereditary breast cancers account for 5-10% of all breast cancers. 5-8 Breast cancer cumulative risk to age 50 years and 70 years in mutation carriers are 49% and 71%, respectively, for BRCA1. 9 BRCA1 expression is also frequently reduced in sporadic cancer. 10-13 BRCA1 encodes an 1863 amino acid (220 kDa) protein that is targeted to the nucleus by 2 nuclear localization sequences, which interact with the nuclear transport signal receptor. 14-17 BRCA1 protein is multifunctional and interacts with other proteins in the nucleus in transcriptional regulation of gene expression, DNA repair and in the maintenance of genomic stability. 1,18 Thus, loss of BRCA1 function may lead to accumulation of chromosomal damage, abnormalities in growth control and tumorigenesis. 19 BRCA1 is regarded as an important central component in regulating multiple biological pathways. 18,20 The function of BRCA1 intersects with the cyclin-dependent kinase inhibitor p27 Kip1 , cyclin D1, the extracellular matrix [21][22][23] and with the estrogen and progesterone pathways in hormonal driven tumor development and progres...

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confidence: 99%

BRCA1 modulates malignant cell behavior, the expression of survivin and chemosensitivity in human breast cancer cells

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Patmasiriwat

Chakrabarty

2009

Intl Journal of Cancer

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Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse

et al. 2001

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Resveratrol, a polyphenol present in wine and grapes, can inhibit tumor cell growth in vitro and tumorigenesis in vivo. Some of its effects have been linked to activation of the p53 tumor suppressor; however, p53 is frequently mutated in tumors, particularly in the common and often therapy-resistant colon cancers. Using the human wild-type p53-expressing HCT116 colon carcinoma cell line and HCT116 cells with both p53 alleles inactivated by homologous recombination, we show in the current study that resveratrol at concentrations comparable to those found in some foods can induce apoptosis independently of p53. The cell death is primarily mitochondria-mediated and not receptor-mediated. No cells survived in cultures continuously exposed to 100 M resveratrol for 120 hr. When compared with 5-FU, resveratrol stimulated p53 accumulation and activity only weakly and with delayed kinetics and neither the increased levels nor the activity affected apoptosis detectably. The apoptosis agonist Bax was overproduced in response to resveratrol regardless of p53 status, yet the kinetics of Bax expression were influenced by p53. Remarkably, apoptosis was preceded by mitochondrial proliferation and signs of epithelial differentiation. Thus, resveratrol triggers a p53-independent apoptotic pathway in HCT116 cells that may be linked to differentiation. The antifungal phytoalexin resveratrol (3,5,4Ј-trihydroxy-transstilbene) is a constituent of many plant species and present at particularly high levels in grapes and wine. 1 As a polyphenol, it is not only a potent inhibitor of radical formation (ED 50 27 M) but acts as a pleiotropic effector molecule to inhibit initiation, promotion and progression of malignant transformation. Resveratrol inhibits the cyclooxygenase (ED 50 15 M) and hydroperoxidase (ED 50 3.7 M) activities of COX-1 and the hydroperoxidase activity of COX-2 (ED 50 85 M). 2 Furthermore, it functions as an inhibitor of platelet aggregation, a modulator of lipid and lipoprotein metabolism 3 and an effective blocker of ribonucleotide reductase (ED 50 100 M) that provides deoxyribonucleotides for DNA synthesis. 4 It also inhibits DNA polymerase 5 and mimics estradiol. 6 Several of these activities constitute the basis for the chemopreventive action of resveratrol, exemplified by its antimutagenic activity in the Ames assay, inhibition of tumorigenesis in a 2-stage murine skin-cancer model 2 and inhibition of cell proliferation in vitro. 7,8 The presence of the functional wild-type form of the p53 tumor suppressor correlates with the sensitivity of mouse tumors and at least some human tumors to therapeutic agents. 9 -11 p53 is stabilized and activated as a transcription factor in response to a variety of cellular stresses, 12 the result being either cell-cycle arrest, mostly through transcriptional activation of the p21 WAF/Cip1 inhibitor of cyclin-dependent kinases, or apoptosis, depending on the cell context. Apoptosis often involves changes to mitochondria. 13 One of the major predictive parameters indicating commitment...

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Bioactive Lipids

Vázquez¹,

Corzo‐Martínez²,

Arranz-Martínez³

et al. 2017

Reference Series in Phytochemistry

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Differentiation-promoting effect of 1-O (2 methoxy) hexadecyl glycerol in human colon cancer cells

Cited by 15 publications

References 40 publications

BRCA1 modulates malignant cell behavior, the expression of survivin and chemosensitivity in human breast cancer cells

BRCA1 modulates malignant cell behavior, the expression of survivin and chemosensitivity in human breast cancer cells

Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse

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