Skp2 is a Promising Therapeutic Target in Breast Cancer

Wang, Zhiwei; Fukushima, Hidefumi; Inuzuka, Hiroyuki; Wan, Lixin; Liu, Pengda; Gao, Daming; Sarkar, Fazlul H.; Wei, Wenyi

doi:10.3389/fonc.2011.00057

Cited by 71 publications

(63 citation statements)

References 114 publications

(223 reference statements)

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“…27, 30, 31 Skp2 expression has been considered as a biomarker of poor prognosis for breast cancer, melanoma, and nasopharyngeal carcinoma. 32, 54, 55 Interestingly, a recent study revealed a possible role for Skp2 in maintaining the CSC-like phenotype of nasopharyngeal carcinoma cells. 56 Because of its oncogenic activity and its role in cancer development, Skp2 has been suggested as a novel and attractive therapeutic target for the cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Salinomycin induces cell death via inactivation of Stat3 and downregulation of Skp2

Kim

Bae

et al. 2013

Cell Death Dis

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Salinomycin has been shown to control breast cancer stem cells, although the mechanisms underlying its anticancer effects are not clear. Deregulation of cell cycle regulators play critical roles in tumorigenesis, and they have been considered as anticancer targets. In this study, we investigated salinomycin effect on cell cycle progression using OVCAR-8 ovarian cancer cell line and multidrug-resistant NCI/ADR-RES and DXR cell lines that are derived from OVCAR-8. Parental OVCAR-8 cells are sensitive to several anticancer drugs, but NCI/ADR-RES and DXR cells are resistant to several anticancer drugs. However, salinomycin caused cell growth inhibition and apoptosis via cell cycle arrest at G1 in all three cell lines. Salinomycin inhibited signal transducer and activator of transcription 3 (Stat3) activity and thus decreased expression of Stat3-target genes, including cyclin D1, Skp2, and survivin. Salinomycin induced degradation of Skp2 and thus accumulated p27Kip1. Knockdown of Skp2 further increased salinomycin-induced G1 arrest, but knockdown of p27Kip1 attenuated salinomycin effect on G1 arrest. Cdh1, an E3 ligase for Skp2, was shifted to nuclear fractions upon salinomycin treatment. Cdh1 knockdown by siRNA reversed salinomycin-induced Skp2 downregulation and p27Kip1 upregulation, indicating that salinomycin activates the APCCdh1–Skp2–p27Kip1 pathway. Concomitantly, si-Cdh1 inhibited salinomycin-induced G1 arrest. Taken together, our data indicate that salinomycin induces cell cycle arrest and apoptosis via downregulation or inactivation of cell cycle-associated oncogenes, such as Stat3, cyclin D1, and Skp2, regardless of multidrug resistance.

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Section: Discussionmentioning

confidence: 99%

Salinomycin induces cell death via inactivation of Stat3 and downregulation of Skp2

Kim

Bae

et al. 2013

Cell Death Dis

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“…Skp2 is an E3 ligase involved in cell-cycle progression by targeting various cell-cycle regulators, including p27, p21, and FOXO1, for degradation. Skp2 is overexpressed in a variety of human cancers including cancers of the breast, colon, and prostate, as well as lymphoma and melanoma [65]. In A549 nonsmall lung carcinoma cells, lycopene-derived metabolites, such as apo-10′-lycopenic acid, can induce cell-cycle arrest at the G 1 /S, transition.…”

Section: Potential Mechanisms Of Actions Of Lycopenementioning

confidence: 99%

Multiple Molecular and Cellular Mechanisms of Action of Lycopene in Cancer Inhibition

Trejo-Solís

Pedraza‐Chaverrí

Torres-Ramos

et al. 2013

Evidence-Based Complementary and Alternative Medicine

120

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Epidemiological studies suggest that including fruits, vegetables, and whole grains in regular dietary intake might prevent and reverse cellular carcinogenesis, reducing the incidence of primary tumours. Bioactive components present in food can simultaneously modulate more than one carcinogenic process, including cancer metabolism, hormonal balance, transcriptional activity, cell-cycle control, apoptosis, inflammation, angiogenesis and metastasis. Some studies have shown an inverse correlation between a diet rich in fruits, vegetables, and carotenoids and a low incidence of different types of cancer. Lycopene, the predominant carotenoid found in tomatoes, exhibits a high antioxidant capacity and has been shown to prevent cancer, as evidenced by clinical trials and studies in cell culture and animal models. In vitro studies have shown that lycopene treatment can selectively arrest cell growth and induce apoptosis in cancer cells without affecting normal cells. In vivo studies have revealed that lycopene treatment inhibits tumour growth in the liver, lung, prostate, breast, and colon. Clinical studies have shown that lycopene protects against prostate cancer. One of the main challenges in cancer prevention is the integration of new molecular findings into clinical practice. Thus, the identification of molecular biomarkers associated with lycopene levels is essential for improving our understanding of the mechanisms underlying its antineoplastic activity.

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“…Numerous studies to date have provided evidence showing the oncogenic potential of SKP2, and its cross-talk with multiple signaling pathways involved in carcinogenesis such as PI3K/AKT, mTOR, ERK, NF k B, Ras/MAPK, and IGF (Wang et al, 2012c). Overexpression of SKP2 can drive quiescent cells to enter the cell cycle (Sutterluty et al, 1999), and promote adhesion-independent growth of cancer cells (Carrano and Pagano, 2001; Signoretti et al, 2002).…”

Section: Skp2mentioning

confidence: 99%

p53, SKP2, and DKK3 as MYCN Target Genes and Their Potential Therapeutic Significance

Chen¹,

Tweddle²

2012

Front. Oncol.

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Neuroblastoma is the most common extra-cranial solid tumor of childhood. Despite significant advances, it currently still remains one of the most difficult childhood cancers to cure, with less than 40% of patients with high-risk disease being long-term survivors. MYCN is a proto-oncogene implicated to be directly involved in neuroblastoma development. Amplification of MYCN is associated with rapid tumor progression and poor prognosis. Novel therapeutic strategies which can improve the survival rates whilst reducing the toxicity in these patients are therefore required. Here we discuss genes regulated by MYCN in neuroblastoma, with particular reference to p53, SKP2, and DKK3 and strategies that may be employed to target them.

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Skp2 is a Promising Therapeutic Target in Breast Cancer

Cited by 71 publications

References 114 publications

Salinomycin induces cell death via inactivation of Stat3 and downregulation of Skp2

Salinomycin induces cell death via inactivation of Stat3 and downregulation of Skp2

Multiple Molecular and Cellular Mechanisms of Action of Lycopene in Cancer Inhibition

p53, SKP2, and DKK3 as MYCN Target Genes and Their Potential Therapeutic Significance

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