Clofibric acid, a peroxisome proliferator–activated receptor α ligand, inhibits growth of human ovarian cancer

Yokoyama, Yoshihiko; Xin, Bing; Shigeto, Tatsuhiko; Umemoto, M; Kasai-Sakamoto, Akiko; Futagami, Masayuki; Tsuchida, Shigeki; Al-Mulla, Fahd; Mizunuma, Hideki

doi:10.1158/1535-7163.mct-06-0722

Cited by 83 publications

(91 citation statements)

References 37 publications

(25 reference statements)

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“…They may be used for maintenance of long-term angiogenesis suppression. Furthermore, our findings support recent studies (11)(12)(13)(14) that suggest that PPAR␣ ligands may be ideally suited to complement conventional modalities for cancer treatment. Specifically, because fenofilerate is commercially available, it could be evaluated as an extension of existing multidrug regimens, notably in metronomic (antiangiogenic) chemotherapy schemes (38,39).…”

Section: Discussionsupporting

confidence: 89%

“…3e and SI Fig. 9), consistent with the decrease of microvessel density in murine tumor models after treatment with PPAR␣ ligands (13,14).…”

Section: Systemic Therapy With Ppar␣ Ligands Inhibits Primary Tumor Gsupporting

confidence: 80%

“…Furthermore, PPAR␣ ligands decrease tumor development in murine colon carcinogenesis (7). Clofibric acid inhibits the growth of human ovarian cancer in mice (13). Most recently, the PPAR␣ agonist WY14643 suppresses tumorigenesis in a PPAR␣-dependent manner (14).…”

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confidence: 99%

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PPARα agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition

Panigrahy

Kaipainen

Huang

et al. 2008

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

244

206

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Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferatoractivated receptor (PPAR)␣ deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPAR␣ would promote tumor growth. Surprisingly, the PPAR␣ agonist fenofibrate potently suppressed primary tumor growth in mice. This effect was not mediated by cancer-cell-autonomous antiproliferative mechanisms but by the inhibition of angiogenesis and inflammation in the host tissue. Although PPAR␣-deficient tumors were still susceptible to fenofibrate, absence of PPAR␣ in the host animal abrogated the potent antitumor effect of fenofibrate. In addition, fenofibrate suppressed endothelial cell proliferation and VEGF production, increased TSP-1 and endostatin, and inhibited corneal neovascularization. Thus, both genetic abrogation of PPAR␣ as well as its activation by ligands cause tumor suppression via overlapping antiangiogenic pathways. These findings reveal the potential utility of the well tolerated PPAR␣ agonists beyond their use as lipid-lowering drugs in anticancer therapy. Our results provide a mechanistic rationale for evaluating the clinical benefits of PPAR␣ agonists in cancer treatment, alone and in combination with other therapies. stroma ͉ inflammation ͉ fibrates ͉ microenvironment P eroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors comprising three isoforms, PPAR␣, PPAR␦, and PPAR␥, which act as ligand-activated transcriptional factors. PPARs play key roles in energy homeostasis by modulating glucose and lipid metabolism and transport (1). PPAR␣ is also critical in inflammation (2) and is the molecular target of the fibrate class of drugs, such as fenofibrate, which act as agonistic ligands of PPAR␣.Long-term administration of certain PPAR␣ agonists (clofibrate and WY14643) induces hepatocarcinogenesis in rodents but not in humans (3). Consequently, PPAR␣ has not been established as a molecular target for cancer therapy by its agonistic ligands. In contrast, PPAR␥ and PPAR␦ agonists have been extensively studied to evaluate their anticancer effects because of their antiproliferative, proapoptotic, antiapoptotic, and differentiation-promoting activity (4). However, recent studies have revealed the expression of PPAR␣ in tumor cells (5, 6), and PPAR␣ ligands suppress the growth of several cancer lines, including colon, breast, endometrial and skin, in vitro (7-10). PPAR␣ ligands also suppress the metastatic potential of melanoma cells in vitro and in vivo (11,12). Furthermore, PPAR␣ ligands decrease tumor development in murine colon carcinogenesis (7). Clofibric acid inhibits the growth of human ovarian cancer in mice (13). Most recently, the PPAR␣ agonist WY14643 suppresses tumorigenesis in a PPAR␣-dependent manner (14).Together, these data suggest that PPAR...

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Section: Discussionsupporting

confidence: 89%

“…3e and SI Fig. 9), consistent with the decrease of microvessel density in murine tumor models after treatment with PPAR␣ ligands (13,14).…”

Section: Systemic Therapy With Ppar␣ Ligands Inhibits Primary Tumor Gsupporting

confidence: 80%

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PPARα agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition

Panigrahy

Kaipainen

Huang

et al. 2008

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

244

206

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“…The human ovarian serous adenocarcinoma cell line SKOV-3 (25) was purchased from American Type Culture Collection (ATCC), and the DISS one was described previously (26). The murine lymphoma cell line EL-4 and murine Lewis lung carcinoma (LLC) were provided from the Cell Resource Center for Biomedical Research, Institute of Development, Aging, and Cancer, Tohoku University (Sendai, Japan).…”

Section: Cells and Cell Culturementioning

confidence: 99%

Vasohibin-2 Expressed in Human Serous Ovarian Adenocarcinoma Accelerates Tumor Growth by Promoting Angiogenesis

Takahashi

Koyanagi

Suzuki

et al. 2012

Molecular Cancer Research

106

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Vasohibin-1 (VASH1) is a VEGF-inducible endothelium-derived angiogenesis inhibitor and VASH2 is its homolog. Our previous analysis revealed that VASH1 is expressed in endothelial cells to terminate angiogenesis, whereas VASH2 is expressed in infiltrating mononuclear cells mobilized from bone marrow to promote angiogenesis in a mouse model of hypoxia-induced subcutaneous angiogenesis. To test the possible involvement of VASH2 in the tumor, we examined human ovarian cancer cells for the presence of VASH2. Immunohistochemical analysis revealed that VASH2 protein was preferentially detected in cancer cells of serous ovarian adenocarcinoma. We then used SKOV-3 and DISS, two representative human serous adenocarcinoma cell lines, and examined the role of VASH2 in the tumor. The knockdown of VASH2 showed little effect on the proliferation of cancer cells in vitro but notably inhibited tumor growth, peritoneal dissemination, and tumor angiogenesis in a murine xenograft model. Next, we stably transfected the human VASH2 gene into two types of murine tumor cells, EL-4 and MLTC-1, in which endogenous VASH2 was absent. When either EL-4 or MLTC-1 cells were inoculated into VASH2 (À/À) mice, the VASH2 transfectants formed bigger tumors when compared with the controls, and the tumor microvessel density was significantly increased. VASH2 stimulated the migration of endothelial cells, and its increased expression in cancer cells is related to the decrease of mir-200b. These results indicate that VASH2 expressed in serous ovarian carcinoma cells promoted tumor growth and peritoneal dissemination by promoting angiogenesis. Mol Cancer Res; 10(9); 1135-46. Ó2012 AACR.

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“…The OVICE cell line that is derived from human clear cell carcinoma was obtained from the Japanese Collection of Research Bioresources Cell Bank (Osaka, Japan) 9. The HRA cells and DISS cells, derived from human epithelial ovarian carcinoma, were generously provided by the National Defense Medical College, Tokorozawa, Japan,10 and Jichi Medical School, Tochigi, Japan11, respectively. All the cells were grown in Roswell Park Memorial Institute (RPMI) medium‐1640 (Sigma‐Aldrich, St. Louis, MO, USA) and supplemented with 10% fetal bovine serum, at 37°C, in a water‐saturated atmosphere with 5% CO 2 and 95% air 12.…”

Section: Methodsmentioning

confidence: 99%

Functional role of the Tau protein in epithelial ovarian cancer cells

Yamauchi

Kobayashi

Oikiri

et al. 2017

Reprod Medicine & Biology

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AimThe microtubule‐associated Tau protein is a marker of paclitaxel sensitivity in ovarian cancer. The aim of the present study was to elucidate the function of the Tau protein in epithelial ovarian cancer.MethodsThe correlation between Tau protein expression and the response to paclitaxel by using several ovarian cancer cell lines was investigated.ResultsA Western blot showed that the expression level of the Tau protein was the highest in the TOV112D cells. A cell‐counting kit showed that the proliferation rates were more inhibited in the cells with down‐regulated Tau protein than in the control cells, both with and without paclitaxel treatment. The proliferation rates of the control cells and the TOV112D cells also were compared with Tau protein overexpression. The level of cell proliferation was more inhibited in the cells that overexpressed the Tau protein, compared to the control cells, both with and without paclitaxel treatment. It was shown that both the down‐regulation and the overexpression of the Tau protein were related to the inhibition of TOV112D cell proliferation. Early and late apoptosis of the TOV112D cells that were transfected with Tau cDNA plasmid construct or Tau small interfering RNA significantly increased.ConclusionThese findings suggest that the molecular targeting of the Tau protein could be a potential treatment for ovarian cancer.

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Clofibric acid, a peroxisome proliferator–activated receptor α ligand, inhibits growth of human ovarian cancer

Abstract: Recent reports have shown that peroxisome proliferatoractivated receptor (PPAR

Cited by 83 publications

References 37 publications

PPARα agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition

PPARα agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition

Vasohibin-2 Expressed in Human Serous Ovarian Adenocarcinoma Accelerates Tumor Growth by Promoting Angiogenesis

Functional role of the Tau protein in epithelial ovarian cancer cells

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