Gene Expression Profiling of Breast, Prostate, and Glioma Cells following Single versus Fractionated Doses of Radiation

Tsai, Mong-Hsun; Cook, John A.; Chandramouli, Gadisetti V.R.; DeGraff, William; Yan, Hailing; Zhao, Shuping; Coleman, C. Norman; Mitchell, James B.; Chuang, Eric Y.

doi:10.1158/0008-5472.can-06-4250

Cited by 172 publications

(150 citation statements)

References 23 publications

(25 reference statements)

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“…However, in a high percentage of tumours and cancer cells (such as PC-3), the p53 gene is functionally inactive. In addition, upon irradiation, expression of proteins related to cell survival pathways, such as EGF or VEGF/Id-1, are strongly induced (Tsai et al, 2007) in a likely attempt to overcome cell stress and reactive oxygen species (ROS) effect. Here, we present the data supporting that the use of P529 could also block the radiationinduced overexpression of survival factors, such as VEGF, Id-1, MMP-2, and MMP-9.…”

Section: Discussionmentioning

confidence: 99%

The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer

et al. 2009

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Radiotherapy (RT) is a common treatment for localised prostate cancer, but can cause important side effects. The therapeutic efficacy of RT can be enhanced by pharmacological compounds that target specific pathways involved in cell survival. This would elicit a similar therapeutic response using lower doses of RT and, in turn, reducing side effects. This study describes the antitumour activity of the novel Akt inhibitor 8-(1-Hydroxy-ethyl)-2-methoxy-3-(4-methoxy-benzyloxy)-benzo[c]chromen-6-one (Palomid 529 or P529) as well as its ability to decrease radiation-activated phospho-Akt (p-Akt) signalling in a prostate cancer model. P529 showed a potent antiproliferative activity in the NCI-60 cell lines panel, with growth inhibitory 50 (GI50) o35 mM. In addition, P529 significantly enhanced the antiproliferative effect of radiation in prostate cancer cells (PC-3). Analysis of signalling pathways targeted by P529 exhibited a decrease in p-Akt, VEGF, MMP-2, MMP-9, and Id-1 levels after radiation treatment. Moreover, the Bcl-2/Bax ratio was also reduced. Treatment of PC-3 tumour-bearing mice with 20 mg kg À1 P529 or 6 Gy radiation dose decreased tumour size by 42.9 and 53%, respectively. Combination of both treatments resulted in 77.4% tumour shrinkage. Decreased tumour growth was due to reduced proliferation and increased apoptosis (as assessed by PCNA and caspase-3 immunostaining). Our results show the antitumour efficacy of P529 alone, and as a radiosensitiser, and suggest that this compound could be used in the future to treat human prostate cancer.

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Section: Discussionmentioning

confidence: 99%

The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer

et al. 2009

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“…Genes upregulated more than fivefold in the mammary glands of MMTV-Cre Brca1 Co/Co mice at day 1 of lactation include Cdkn1A (p21, up 16.3-fold), a cell cycle regulated that has previously been shown to be upregulated upon Brca1 repression (Hakem et al, 1996) and that has been implicated in breast cancer (Weiss, 2003); interferon-stimulated gene 15 (Isg15, up 10.9-fold) and the gene encoding the Isg15-interacting protein Ubp43 (up eightfold), the former being a ubiquitin-like gene implicated in immune response to viruses and in breast cancer (Bektas et al, 2008); oligoadenylate synthetase 1G (up 9.2-fold) and 1A (up 5.7-fold), an interferon-induced enzyme implicated in nucleotide metabolism and expressed in the mammary gland (Maia et al, 2008) and induced upon irradiation of human breast cancer cell lines (Tsai et al, 2007); and c-kit (up 5.58-fold), a hematopoietic stem cell marker that is overexpressed in undifferentiated mammary tumours (Tsuda et al, 2005) and functions as an oncogene in mammary epithelial cells (Tsuda et al, 2005;Raafat et al, 2007). Taken together, these genes suggest a role for Brca1 in the immune response and cancer.…”

Section: (A) Endogenousmentioning

confidence: 99%

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

et al. 2010

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Disruption of the breast cancer susceptibility gene Brca1 results in defective lobular-alveolar development in the mammary gland and a predisposition to breast tumourigenesis in humans and in mice. Recent evidence suggests that BRCA1 loss in humans is associated with an expansion of the luminal progenitor cell compartment in the normal breast and tumours with a luminal progenitorlike expression profile. To further investigate the role of BRCA1 in the mammary gland, we examined the consequences of Brca1 loss in mouse mammary epithelial cells in vitro and in vivo. Here, we show that Brca1 loss is associated with defective morphogenesis of SCp2 and HC11 mouse mammary epithelial cell lines and that in the MMTV-Cre Brca1 Co/Co mouse model of Brca1 loss, there is an accumulation of luminal progenitor (CD61 þ CD29 lo CD24 þ ) cells during pregnancy. By day 1 of lactation, there are marked differences in the expression of 1379 genes, with most significantly altered pathways and networks, including lactation, the immune response and cancer. One of the most differentially expressed genes was the luminal progenitor marker, c-kit. Immunohistochemical analysis revealed that the increase in c-kit levels is associated with an increase in c-kit positivity. Interestingly, an inverse association between Brca1 and c-kit expression was also observed during mammary epithelial differentiation, and small interfering RNA-mediated knockdown of Brca1 resulted in a significant increase in c-kit mRNA levels. We found no evidence that c-kit plays a direct role in regulating differentiation of HC11 cells, suggesting that Brca1-mediated induction of c-kit probably contributes to Brca1-associated tumourigenesis via another cellular process, and that c-kit is likely to be a marker rather than a mediator of defective lobular-alveolar development resulting from Brca1 loss.

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“…innate immunity | cytoplasmic sensor | interferon beta | DHX58 S everal studies have shown that the response of tumor cells to ionizing radiation (IR) is associated with IFN-mediated signaling (1)(2)(3)(4)(5)(6). IFN signaling leads to the induction of multiple IFN stimulated genes (ISGs) (7,8) and activates growth arrest and cell death in exposed cell populations (9).…”

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confidence: 99%

RIG-I–like receptor LGP2 protects tumor cells from ionizing radiation

Widau¹,

Parekh²,

Ranck³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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An siRNA screen targeting 89 IFN stimulated genes in 14 different cancer cell lines pointed to the RIG-I (retinoic acid inducible gene I)-like receptor Laboratory of Genetics and Physiology 2 (LGP2) as playing a key role in conferring tumor cell survival following cytotoxic stress induced by ionizing radiation (IR). Studies on the role of LGP2 revealed the following: (i) Depletion of LGP2 in three cancer cell lines resulted in a significant increase in cell death following IR, (ii) ectopic expression of LGP2 in cells increased resistance to IR, and (iii) IR enhanced LGP2 expression in three cell lines tested. Studies designed to define the mechanism by which LGP2 acts point to its role in regulation of IFNβ. Specifically (i) suppression of LGP2 leads to enhanced IFNβ, (ii) cytotoxic effects following IR correlated with expression of IFNβ inasmuch as inhibition of IFNβ by neutralizing antibody conferred resistance to cell death, and (iii) mouse embryonic fibroblasts from IFN receptor 1 knockout mice are radioresistant compared with wild-type mouse embryonic fibroblasts. The role of LGP2 in cancer may be inferred from cumulative data showing elevated levels of LGP2 in cancer cells are associated with more adverse clinical outcomes. Our results indicate that cytotoxic stress exemplified by IR induces IFNβ and enhances the expression of LGP2. Enhanced expression of LGP2 suppresses the IFN stimulated genes associated with cytotoxic stress by turning off the expression of IFNβ.innate immunity | cytoplasmic sensor | interferon beta | DHX58

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Gene Expression Profiling of Breast, Prostate, and Glioma Cells following Single versus Fractionated Doses of Radiation

Cited by 172 publications

References 23 publications

The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer

The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

RIG-I–like receptor LGP2 protects tumor cells from ionizing radiation

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