Increased angiogenesis inCdk4R24C/R24C:Apc+/Minintestinal tumors

Abedin, Zahidur; Ma, Zhongjie; Reddy, E. Premkumar

doi:10.4161/cc.9.12.12055

Cited by 18 publications

(10 citation statements)

References 38 publications

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“…Cyclin G overexpression is a frequent event in colorectal cancer [32]. Moreover, CDK4 is a cell cycle regulator involved in early G1 cell cycle progression and has a direct role in angiogenesis in vivo [33]. Reduced expression of the cell cycle inhibitor p27 was associated with malignant transformation of the ovarian epithelium and FIGO stage [34].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Ras Homologous C (RhoC) Induces Malignant Transformation of Hepatocytes In Vitro and in Nude Mouse Xenografts

Xie

Zhu

et al. 2013

PLoS ONE

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Ras homologous C (RhoC) is expressed in various cancers, including hepatocellular carcinoma (HCC). In this study, we first analyzed RhoC expression in 46 HCC tissue specimens and found that RhoC expression was significantly increased in HCC tissues compared to the adjacent normal liver tissues. Next, we investigated the role of RhoC in malignant transformation of normal hepatocytes. The HL7702 cell line was stably transfected with a RhoC expression vector and then subjected to cell proliferation, differentiation, colony formation, migration and invasion assays, as well as nude mouse xenograft assays. Gene expressions in these cells were determined using RT-PCR and Western blot. Overexpression of RhoC significantly promoted proliferation and anchorage-independent growth of HL7702 cells, but suppressed cell differentiation, as compared with the parental cells and the empty vector-transfected control cells. Moreover, RhoC overexpression induced migration and invasion of HL7702 cells in vitro. Molecularly, RhoC increased the expression of cell cycle-related genes, matrix metalloprotease 2 (MMP2), MMP9 and vascular endothelial growth factor (VEGF). In addition, RhoC-transfected cells formed tumors in nude mice, whereas vector-transfected HL7702 cells did not form any tumors in nude mice. This study demonstrated the role of RhoC overexpression in malignant transformation of normal human hepatocytes, suggesting that RhoC may function as an oncogene in hepatocytes.

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Section: Discussionmentioning

confidence: 99%

Overexpression of Ras Homologous C (RhoC) Induces Malignant Transformation of Hepatocytes In Vitro and in Nude Mouse Xenografts

Xie

Zhu

et al. 2013

PLoS ONE

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“…Besides regulating cell cycle progression through the pRb/E2F pathway and the G1-S checkpoint, 1 non-cell-cycle effects of CDK4/6 include direct activation of vascular endothelial growth factor (VEGF) transcription, promotion of angiogenesis and nuclear factor (NF)-kB activation via the p65 transcription factor. [2][3][4] PD0332991 (palbociclib) is a highly selective small molecular inhibitor of CDK4 and 6. Palbociclib was approved by the FDA in 2015 in combination with letrozole as initial hormone-plus CDK-targeted therapy for post-menopausal women with ER(C)/Her2(¡) advanced breast cancer.…”

Section: Introductionmentioning

confidence: 99%

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

et al. 2017

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Hypoxia is an inherent impediment to cancer therapy. Palbociclib, a highly selective inhibitor for CDK4/6, has been tested in numerous clinical trials and has been approved by the FDA. We previously reported that CDK inhibitors can destabilize HIF1a regardless of the presence of hypoxia and can sensitize tumor cells to TRAIL through dual blockade of CDK1 and GSK-3b. To translate this knowledge into a cancer therapeutic strategy, we investigated the therapeutic effects and molecular mechanisms of CDK inhibition against colon cancer cells under normoxia and hypoxia. We found that palbociclib sensitizes colon cancer cells to hypoxia-induced apoptotic resistance via deregulation of HIF-1a accumulation. In addition to inhibition of cell proliferation, we observed that palbociclib promotes colon cancer cell death regardless of the presence of hypoxia at a comparatively high concentration via regulating ERK/GSK-3b signaling and GSK-3b expression. Furthermore, palbociclib synergized with irinotecan in a variety of colon cancer cell lines with various molecular subtypes via deregulating irinotecan-induced Rb phosphorylation and reducing HIF-1a accumulation under normoxia or hypoxia. Collectively, our findings provide a novel combination therapy strategy against hypoxic colon cancer cells that may be further translated in the clinic.

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“…115 In addition to melanomas, CDK4 R24C female mice develop severe mammary duct dilation and a high incidence of mammary tumors, which are often very aggressive with a large tumor burden. 17 The majority of the mammary tumors analyzed were adenosquamous carcinomas with papillary and cribriform elements or adenocarcinomas and adenoacanthomas with squamous differentiation.…”

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confidence: 99%

CDK4: A Key Player in the Cell Cycle, Development, and Cancer

2012

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The cell cycle is regulated in part by cyclins and their associated serine/threonine cyclin-dependent kinases, or CDKs. CDK4, in conjunction with the D-type cyclins, mediates progression through the G 1 phase when the cell prepares to initiate DNA synthesis. Although CDK4-null mutant mice are viable and cell proliferation is not significantly affected in vitro due to compensatory roles played by other CDKs, this gene plays a key role in mammalian development and cancer. This review discusses the role that CDK4 plays in cell cycle control, normal development, and tumorigenesis as well as how small molecule inhibitors of CDK4 can be used to treat disease.

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Increased angiogenesis inCdk4^R24C/R24C:Apc^+/Minintestinal tumors

Cited by 18 publications

References 38 publications

Overexpression of Ras Homologous C (RhoC) Induces Malignant Transformation of Hepatocytes In Vitro and in Nude Mouse Xenografts

Overexpression of Ras Homologous C (RhoC) Induces Malignant Transformation of Hepatocytes In Vitro and in Nude Mouse Xenografts

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

CDK4: A Key Player in the Cell Cycle, Development, and Cancer

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