Reduction of Orc6 Expression Sensitizes Human Colon Cancer Cells to 5-Fluorouracil and Cisplatin

Gavin, Elaine; Song, Bo; Wang, Yuan; Xi, Yaguang; Ju, Jingfang

doi:10.1371/journal.pone.0004054

Cited by 35 publications

(35 citation statements)

References 23 publications

(27 reference statements)

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“…The results show that all six ORC subunits were overexpressed and had an elevated association with chromatin in the transformed compared to normal cells, as was previously shown for ORC1, ORC2, and ORC4 [McNairn and Gilbert, 2005], as well as ORC6 in colorectal cancer [Gavin et al, 2008]. Similarly, increased protein levels and chromatin association were observed in the transformed cells for Cdc6 and Cdt1, in agreement with previous studies using normal and tumor lung cell specimens, where the overexpression of Cdc6 and Cdt1 promoted malignant behavior [Karakaidos et al, 2004; Liontos et al, 2007].…”

Section: Discussionsupporting

confidence: 81%

Comparative analysis of pre‐replication complex proteins in transformed and normal cells

Paola

Zannis‐Hadjopoulos

2012

J of Cellular Biochemistry

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This study examines the abundance of the major protein constituents of the pre-replication complex (pre-RC), both genome-wide and in association with specific replication origins, namely the lamin B2, c-myc, 20mer1, and 20mer2 origins. Several pre-RC protein components, namely ORC1-6, Cdc6, Cdt1, MCM4, MCM7, as well as additional replication proteins, such as Ku70/86, 14-3-3, Cdc45, and PCNA, were comparatively and quantitatively analyzed in both transformed and normal cells. The results show that these proteins are overexpressed and more abundantly bound to chromatin in the transformed compared to normal cells. Interestingly, the 20mer1, 20mer2, and c-myc origins exhibited a two- to threefold greater origin activity and a two- to threefold greater in vivo association of the pre-RC proteins with these origins in the transformed cells, whereas the origin associated with the housekeeping lamin B2 gene exhibited both similar levels of activity and in vivo association of these pre-RC proteins in both cell types. Overall, the results indicate that cellular transformation is associated with an overexpression and increased chromatin association of the pre-RC proteins. This study is significant, because it represents the most systematic comprehensive analysis done to date, using multiple replication proteins and different replication origins in both normal and transformed cell lines.

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Section: Discussionsupporting

confidence: 81%

Comparative analysis of pre‐replication complex proteins in transformed and normal cells

Paola

Zannis‐Hadjopoulos

2012

J of Cellular Biochemistry

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“…Our results obtained by evaluation of cell cycle kinetics revealed that cells with high Smad4 expression were arrested in the G2-M phase under 5-FU treatment, owing to inhibition of the CDC2/cyclin B/survivin cascade. Accumulation of cells in the G1/S phase may result in resistance to 5-FU treatment, which is consistent with previous studies (34)(35)(36). Smad4 reduced the CDC2/cyclin B complex and survivin in both the CT26 and SW620 cells, through the downregulation of the PI3K/Akt pathway, resulting in cell cycle arrest and cell apoptosis.…”

Section: Discussionsupporting

confidence: 91%

Smad4 sensitizes colorectal cancer to 5-fluorouracil through cell cycle arrest by inhibiting the PI3K/Akt/CDC2/survivin cascade

Zhang

Leng

et al. 2015

Oncology Reports

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Abstract. 5-Fluorouracil (5-FU), a cell cycle-specific antimetabolite, is one of the most commonly used chemotherapeutic agents for colorectal cancer (CRC). Yet, resistance to 5-FU-based chemotherapy is still an obstacle to the treatment of this malignancy. Mutation or loss of Smad4 in CRC is pivotal for chemoresistance. However, the mechanism by which Smad4 regulates the chemosensitivity of CRC remains unclear. In the present study, we investigated the role of Smad4 in the chemosensitivity of CRC to 5-FU, and whether Smad4-regulated cell cycle arrest is involved in 5-FU chemoresistance. We used Smad4-expressing CT26 and Smad4-null SW620 cell lines as experimental models, by knockdown or transgenic overexpression. Cells or tumors were treated with 5-FU to determine chemosensitivity by cell growth, tumorigenicity assay and a mouse model. Cell cycle distribution was examined with flow cytometric analysis, and cell cycle-related proteins were examined by western blotting. Smad4 deficiency in CT26 and SW620 cells induced chemoresistance to 5-FU both in vitro and in vivo. Smad4 deficiency attenuated G1 or G2 cell cycle arrest by activating the PI3K/Akt/CDC2/survivin pathway. The PI3K inhibitor, LY294002, reversed the activation of the Akt/CDC2/survivin cascade in the Smad4-deficient cells, while it had little effect on cells with high Smad4 expression. In conclusion, we discovered a novel mechanism mediated by Smad4 to trigger 5-FU chemosensitivity through cell cycle arrest by inhibiting the PI3K/Akt/CDC2/survivin cascade. The present study also implies that LY294002 has potential therapeutic value to reverse the chemosensitivity of CRC with low Smad4 expression.

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“…Finally, we measured p21 and NAG-1 expression in p53 knock-out cells. NAG-1 and p21 have been known to be induced by p53 protein at the transcriptional level (16–17). HCT-116 p53−/− cells were treated with apigenin for 24 hr at 10 μM concentration.…”

Section: Resultsmentioning

confidence: 99%

Molecular targets of apigenin in colorectal cancer cells: Involvement of p21, NAG-1 and p53

Zhong

Krisanapun

Lee

et al. 2010

European Journal of Cancer

102

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Persuasive epidemiological and experimental evidence suggests that dietary flavonoids have anticancer activity. Since conventional therapeutic and surgical approaches have not been able to fully control the incidence and outcome of most cancer types, including colorectal neoplasia, there is an urgent need to develop alternative approaches for the management of cancer. We sought to develop the best flavonoids for the inhibition of cell growth, and apigenin (flavone) proved the most promising compound in colorectal cancer cell growth arrest. Subsequently, we found that pro-apoptotic proteins (NAG-1 and p53) and cell cycle inhibitor (p21) were induced in the presence of apigenin, and kinase pathways, including PKCδ and ataxia telangiectasia mutated (ATM), play an important role in activating these proteins. The data generated by in vitro experiments were confirmed in an animal study using APC MIN+ mice. Apigenin is able to reduce polyp numbers, accompanied by increasing p53 activation through phosphorylation in animal models. Our data suggest apparent beneficial effects of apigenin on colon cancer. Kew Word

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Reduction of Orc6 Expression Sensitizes Human Colon Cancer Cells to 5-Fluorouracil and Cisplatin

Cited by 35 publications

References 23 publications

Comparative analysis of pre‐replication complex proteins in transformed and normal cells

Comparative analysis of pre‐replication complex proteins in transformed and normal cells

Smad4 sensitizes colorectal cancer to 5-fluorouracil through cell cycle arrest by inhibiting the PI3K/Akt/CDC2/survivin cascade

Molecular targets of apigenin in colorectal cancer cells: Involvement of p21, NAG-1 and p53

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