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  • REVIEW

    Beyond peroxisome proliferator-activatedreceptor c signaling: the multi-facets ofthe antitumor effect of thiazolidinediones

    J-R Weng1;2 , C-Y Chen3 ;4, J J Pinzone5, M D Ringel5 and C-S Chen6

    1Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan2China Medical University Hospital, Taichung 404, Taiwan3Department of Family Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan4Division of Gerontology Research, National Health Research Institutes, Taipei, Taiwan5Divisions of Endocrinology and Oncology, Department of Internal Medicine and 6Division of Medicinal Chemistry and Pharmacognosy,

    College of Pharmacy, Parks Hall, Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210, USA

    (Requests for offprints should be addressed to C-S Chen; Email: chen.844@osu.edu

    Abstract

    Certain members of the thiazolidinedione (TZD) family of the peroxisome proliferator-activatedreceptor g (PPARg) agonists, such as troglitazone and ciglitazone, exhibit antitumor activities;however, the underlying mechanism remains inconclusive. Substantial evidence suggests that theantiproliferative effect of these TZD members in cancer cells is independent of PPARg activation.To discern the role of PPARg in the antitumor effects of TZDs, we have synthesized PPARg-inactive TZD analogs which, although devoid of PPARg activity, retain the ability to induce apoptosiswith a potency equal to that of their parental TZDs in cancer cell lines with varying PPARg expressionstatus. Mechanistic studies from this and other laboratories have further suggested that troglitazoneand ciglitazone mediate antiproliferative effects through a complexity of PPARg-independentmechanisms. Evidence indicates that troglitazone and ciglitazone block BH3 domain-mediatedinteractions between the anti apoptotic Bcl-2 (B-cell leukemia/lymphoma 2) members Bcl-2/Bcl-xLand proapoptotic Bcl-2 members. Moreover, these TZDs facilitate the degradation of cyclin D1and caspase-8-related FADD-like IL-l-converting enzyme (FLICE)-inhibitory protein throughproteasome-mediated proteolysis, and down-regulate the gene expression of prostate-specificantigen gene expression by inhibiting androgen activation of the androgen response elements inthe promoter region. More importantly, dissociation of the effects of TZDs on apoptosis from theiroriginal pharmacological activity (i.e. PPARg activation) provides a molecular basis for theexploitation of these compounds to develop different types of molecularly targeted anticanceragents. These TZD-derived novel therapeutic agents, alone or in combination with other anticancerdrugs, have translational relevance in fostering effective strategies for cancer treatment.

    Endocrine-Related Cancer (2006) 13 401413

    Introduction

    Thiazolidinediones (TZDs), including troglitazone(Rezulin), rosiglitazone (Avandia), pioglitazone(Actos), and ciglitazone, are synthetic ligands forthe peroxisome proliferator-activated receptor g(PPARg) (for review see Day 1999) (Fig. 1). Thisfamily of PPARg agonists improves insulin sensitivityby increasing transcription of certain insulin-sensitivegenes involved in the metabolism and transportof lipids in adipocytes, such as lipoprotein lipase,adipocyte fatty acid-binding protein, acyl-CoA

    synthase, and fatty acid transport protein (Koeffler2003). In addition, TZDs have been demonstrated topromote the differentiation of preadipocytes bymimicking certain genomic effects of insulin onadipocytes (Tontonoz et al. 1994), and to regulateglucose homeostasis (Saltiel & Olefsky 1996). Con-sequently, the TZDs offer a new type of oral therapyin type II diabetes to reduce insulin resistance and toassist glycemic control.

    Recent evidence indicates that certain TZDmembers, especially troglitazone and ciglitazone,exhibit moderate antiproliferative activities against

    Endocrine-Related Cancer (2006) 13 401413 DOI:10.1677/erc.1.011821351-0088/06/013401 # 2006 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org

    Endocrine-Related Cancer (2006) 13 401413

  • many epithelial-derived human cancer cell linesincluding those of prostate (Kubota et al. 1998),breast (Yin et al. 2001), colon (Kato et al. 2004),thyroid (Ohta et al. 2001), lung (Tsubouchi et al.2000), and pituitary carcinoma (Heaney et al. 2003).This growth inhibition was linked to the G1 phasecell cycle arrest through the up-expression of thecyclin-dependent kinase inhibitors p21 and p27(Koga et al. 2001, 2003, Takeuchi et al. 2002, Yoshi-zawa et al. 2002, Bae et al. 2003) and/or repressionof cyclin D1 expression (Wang et al. 2001, Yin et al.2001, Lapillonne et al. 2003, Qin et al. 2003). Mean-while, data from this and other laboratories haveindicated that normal prostate epithelial cells (notshown) and T lymphocytes (Harris & Phipps 2002)are more resistant to apoptotic induction by theseTZDs. In the light of this cancer-specific effect, thepotential use of these PPARg agonists as chemo-preventive agents has received much attention (for areview see Badawi & Badr 2002, Kopelovich et al.2002, Smith & Kantoff 2002, Bull 2003, Koeffler2003, Leibowitz & Kantoff 2003, Grommes et al.2004, Jiang et al. 2004). Moreover, animal modelstudies have demonstrated the in vivo efficacy oftroglitazone in colon, prostate, and liver cancers(Kubota et al. 1998, Sarraf et al. 1998, Yu et al.2006) and that of rosiglitazone in pituitary tumors(Henry et al. 2000, Heaney et al. 2002). Despite theseadvances, the mechanism underlying the antitumoreffects of TZD remains unclear. As PPARg-mediatedeffects of TZDs promote the differentiation ofpreadipocytes, one school of thought attributes the

    same mechanism to the terminal differentiation andcell cycle arrest of tumor cells (Tontonoz et al.1997). However, the PPARg-target genes thatmediate the antiproliferative effects remain elusive,as genomic responses to PPARg activation in cancercells are highly complicated (Gupta et al. 2001).Reported causal mechanisms include attenuatedexpression of protein phosphatase 2A (Altiok et al.1997), cyclins D1 and E, inflammatory cytokinesand transcription factors (Koeffler 2003), andincreased expression of an array of gene productslinked to growth regulation and cell maturation(Gupta et al. 2001).

    On the other hand, several lines of evidence havesuggested that the inhibitory effect of TZDs ontumor cell proliferation is independent of PPARgactivation. For example, sensitivity of cancer cellsto TZD-induced growth inhibition does notcorrelate with the level of PPARg expression, andthere exists a three orders of magnitude discrepancybetween the concentration required to produceantitumor effects and that to modify insulin action(Day 1999). In addition, the in vitro antitumoreffects appear to be structure specific irrespective oftheir potency in PPARg activation, i.e. troglitazoneand ciglitazone are active while rosiglitazone andpioglitazone are not. To date, an array of non-PPARg targets has been implicated in the antitumoractivities of troglitazone and/or ciglitazone indifferent cell systems, which include intracellularCa2 stores (Palakurthi et al. 2001), phosphorylatingactivation of extracellular signal-regulated kinases(Gouni-Berthold et al. 2001, Takeda et al. 2001),c-Jun N-terminal protein kinase, and p38 (Bae &Song 2003), up-regulation of early growthresponse-1 (Baek et al. 2003), the cyclin-dependentkinase (CDK) inhibitors p27kip1 (Motomura et al.2000) and p21WAF=CIP1 (Sugimura et al. 1999), thetumor suppressor protein p53 and the p53-responsive stress protein Gadd45 (Okura et al.2000), and altered expression of B-cell leukemia/lymphoma 2(Bcl-2) family members (Bae & Song2003). However, some of these targets appear to becell type specific due to differences in signalingpathways regulating cell growth and survival indifferent cell systems.

    In considering the translational potential of usingPPARg ligand in cancer prevention and therapy, ourresearch has focused on elucidating the mechanismsunderlying the antitumor effect of TZDs. In thefollowing sections, evidence that dissociates theeffect of TZDs on apoptosis from PPARg-activatingactivity is presented. This review also provides an

    Figure 1 Chemical structures of troglitazone, ciglitazone,

    rosiglitazone, and pioglitazone, and their respective

    PPARg-inactive 2 derivatives (2-TG, 2-CG, 2-RG, and2-PG). The introduction of the double bond adjoining the

    terminal thiazolidinedione ring results in the abrogation of the

    PPARg ligand property.

    J-R Weng et al.: PPARg-independent antitumor effects of thiazolidinediones

    402 www.endocrinology-journals.org

  • overview of recent findings from this and otherlaboratories concerning plausible PPARg-indepen-dent targets that underlie TZD-mediated apoptosis.Equally importantly, the use of TZDs as a molecularplatform to develop novel mechanism-based thera-peutic agents will be discussed.

    Demonstration of PPAR-independentantiproliferative effects of TZDs

    Wehypothesized that if TZDsmediate antitumor effectsindependently of PPARg, one would be able to disso-ciate these two pharmacological activities via structuralmodifications of these molecules. This premise wascorroborated by the development of a novel class ofPPARg-inactiveTZDanalogs,whichwas accomplishedby introducing a double bond adjoining the terminalthiazolidine-2,4-dione ring (Fig. 1) (Shiau et al. 2005).Two lines of evidence indicate that this structuralmodification abrogated the ligand-binding ability ofPPARg. First, these 2 analogs (5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl-methoxy)-benzylidene]-2,4-thiazolidinedione (2-TG), 5-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-benzylidene}-2,4-thiazo-lidinedione (2-RG), 5-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzyli