Peroxisome Proliferator–Activated Receptor α Activation Decreases Metastatic Potential of Melanoma Cells <i>In vitro</i> via Down-Regulation of Akt

Grabacka, Maja; Płonka, Przemysław M.; Urbańska, Krystyna; Reiss, Krzysztof

doi:10.1158/1078-0432.ccr-05-2556

Cited by 139 publications

(157 citation statements)

References 51 publications

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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%

“…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).…”

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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%

mentioning

confidence: 99%

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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“…Time-lapse experiments revealed that fenofibrate inhibited 'contactstimulated' motility of DU-145 cells. An inhibitory effect of fenofibrate on the invasiveness of melanoma (12,13) and glioblastoma cell migration (18) has previously been demonstrated. These experiments, however, did not address the problem of 'contact-stimulated' cell motility and, moreover, described PPARα-dependent cell responses to fenofibrate.…”

Section: Discussionmentioning

confidence: 89%

“…Among them, fenofibrate is commonly used in the prevention of arteriosclerosis as a lipid-lowering drug (9). It is of interest that fibrates in general exert a wide range of anti-cancer properties (10)(11)(12)(13)(14). In particular, fenofibrate was shown to interfere with the growth and survival of different cancer cell types in a manner dependent on the activation of peroxisome-proliferator activated receptor-α (PPARα) (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

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Fenofibrate attenuates contact-stimulated cell motility and gap junctional coupling in DU-145 human prostate cancer cell populations

Madeja

2011

Oncol Rep

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Abstract. In the present study, we investigated the effects of fenofibrate on the invasive potential of DU-145 human prostate cancer cells in the context of gap junctional intercellular coupling and the formation of reactive oxygen species. Timelapse analyses of cell motility, accompanied by tests of cell viability, membrane microviscosity, reactive oxygen species accumulation and the function of gap junctional protein connexin 43 were performed in monolayer cultures of DU-145 cells following fenofibrate administration. Fenofibrate inhibited the motility of DU-145 cells and attenuated gap junctional intercellular coupling in a manner independent of its effects on cell viability, PPARα activation and cell membrane microviscosity. Instead, N-acetyl-L-cysteine, a scavenger of reactive oxygen species, restored cell motility and gap junctional coupling in fenofibrate-treated DU-145 cell populations. These data indicate that two parameters crucial for cancer cell metastatic potential, i.e. cell motility and gap junctional coupling, are inhibited by fenofibrate. Thus, fenofibrate affects prostate cancer cell invasion via an orchestrated action on versatile cancer cell properties determining this process. A novel mechanism of anti-invasive activity of fenofibrate, which depends on its interference with cell motility and the function of gap junctions regulated by reactive oxygen species, is suggested.

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Role of Peroxisome Proliferator‐Activated Receptors in Inflammation and Angiogenesis

Acharya¹

2017

Gene Regulation, Epigenetics and Hormone Signaling

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Peroxisome Proliferator–Activated Receptor α Activation Decreases Metastatic Potential of Melanoma Cells In vitro via Down-Regulation of Akt

Cited by 139 publications

References 51 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

Fenofibrate attenuates contact-stimulated cell motility and gap junctional coupling in DU-145 human prostate cancer cell populations

Role of Peroxisome Proliferator‐Activated Receptors in Inflammation and Angiogenesis

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