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• W2022131162 abstract "Cancer cells gain growth advantages in the microenvironment by shifting cellular metabolism to aerobic glycolysis, the so-called Warburg effect. There is a growing interest in targeting aerobic glycolysis for cancer therapy by exploiting the differential susceptibility of malignant versus normal cells to glycolytic inhibition, of which the proof-of-concept is provided by the in vivo efficacy of dietary caloric restriction and natural product-based energy restriction-mimetic agents (ERMAs) such as resveratrol and 2-deoxyglucose in suppressing carcinogenesis in animal models. Here, we identified thiazolidinediones as a novel class of ERMAs in that they elicited hallmark cellular responses characteristic of energy restriction, including transient induction of Sirt1 (silent information regulator 1) expression, activation of the intracellular fuel sensor AMP-activated protein kinase, and endoplasmic reticulum stress, the interplay among which culminated in autophagic and apoptotic death. The translational implications of this finding are multifold. First, the novel function of troglitazone and ciglitazone in targeting energy restriction provides a mechanistic basis to account for their peroxisome proliferator-activated receptor γ-independent effects on a broad spectrum of signaling targets. Second, we demonstrated that Sirt1-mediated up-regulation of β-transducin repeat-containing protein-facilitated proteolysis of cell cycle- and apoptosis-regulatory proteins is an energy restriction-elicited signaling event and is critical for the antitumor effects of ERMAs. Third, it provides a molecular rationale for using thiazolidinediones as scaffolds to develop potent ERMAs, of which the proof-of-principle is demonstrated by OSU-CG12. OSU-CG12, a peroxisome proliferator-activated receptor γ-inactive ciglitazone derivative, exhibits 1- and 3-order of magnitude higher potency in eliciting starvation-like cellular responses relative to resveratrol and 2-deoxyglucose, respectively. Cancer cells gain growth advantages in the microenvironment by shifting cellular metabolism to aerobic glycolysis, the so-called Warburg effect. There is a growing interest in targeting aerobic glycolysis for cancer therapy by exploiting the differential susceptibility of malignant versus normal cells to glycolytic inhibition, of which the proof-of-concept is provided by the in vivo efficacy of dietary caloric restriction and natural product-based energy restriction-mimetic agents (ERMAs) such as resveratrol and 2-deoxyglucose in suppressing carcinogenesis in animal models. Here, we identified thiazolidinediones as a novel class of ERMAs in that they elicited hallmark cellular responses characteristic of energy restriction, including transient induction of Sirt1 (silent information regulator 1) expression, activation of the intracellular fuel sensor AMP-activated protein kinase, and endoplasmic reticulum stress, the interplay among which culminated in autophagic and apoptotic death. The translational implications of this finding are multifold. First, the novel function of troglitazone and ciglitazone in targeting energy restriction provides a mechanistic basis to account for their peroxisome proliferator-activated receptor γ-independent effects on a broad spectrum of signaling targets. Second, we demonstrated that Sirt1-mediated up-regulation of β-transducin repeat-containing protein-facilitated proteolysis of cell cycle- and apoptosis-regulatory proteins is an energy restriction-elicited signaling event and is critical for the antitumor effects of ERMAs. Third, it provides a molecular rationale for using thiazolidinediones as scaffolds to develop potent ERMAs, of which the proof-of-principle is demonstrated by OSU-CG12. OSU-CG12, a peroxisome proliferator-activated receptor γ-inactive ciglitazone derivative, exhibits 1- and 3-order of magnitude higher potency in eliciting starvation-like cellular responses relative to resveratrol and 2-deoxyglucose, respectively. IntroductionThiazolidinediones (TZDs) 2The abbreviations used are: TZDthiazolidinedioneERMAenergy restriction-mimetic agentPPARperoxisome proliferator-activated receptorTrCPtransducin repeat-containing proteinARandrogen receptorERestrogen receptor2-DG2-deoxyglucoseAMPKAMP-activated protein kinasePrECprostate epithelial cellGFPgreen fluorescent proteinPARPpoly(ADP-ribose) polymeraseERKextracellular signal-regulated kinasemTORmammalian homolog of target of rapamycinTSCtuberous sclerosis complexLClight chaineIFeukaryotic translation initiation factorAtgautophagy-related geneHAhemagglutininGADDgrowth arrest and DNA damage-inducible genesiRNAsmall interfering RNAshRNAsmall hairpin RNAWTwild typeRTreverse transcriptionPBSphosphate-buffered salineMTT3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)LDHlactate dehydrogenase. are selective ligands for the nuclear transcription factor peroxisome proliferator-activated receptor (PPAR) γ (1.Yki-Järvinen H. N. Engl. J. Med. 2004; 351: 1106-1118Crossref PubMed Scopus (1880) Google Scholar, 2.Panchapakesan U. Chen X.M. Pollock C.A. Nat. Clin. Pract. Nephrol. 2005; 1: 33-43Crossref PubMed Scopus (44) Google Scholar). These TZDs improve insulin sensitivity by transcriptional activation of insulin-sensitive genes involved in glucose homeostasis, fatty acid metabolism, and triacylglycerol storage in adipocytes and promote the differentiation of preadipocytes by mimicking the genomic effects of insulin (3.Olefsky J.M. J. Clin. Invest. 2000; 106: 467-472Crossref PubMed Scopus (504) Google Scholar, 4.Sharma A.M. Staels B. J. Clin. Endocrinol. Metab. 2007; 92: 386-395Crossref PubMed Scopus (395) Google Scholar). Moreover, TZD-mediated PPARγ activation has been shown to promote the differentiation of preadipocytes by mimicking the genomic effects of insulin on adipocytes and to modulate the expression of adiponectin, pro-inflammatory cytokines like interleukin-6 and tumor necrosis factor α and a host of endocrine regulators in adipocytes and macrophages (3.Olefsky J.M. J. Clin. Invest. 2000; 106: 467-472Crossref PubMed Scopus (504) Google Scholar, 4.Sharma A.M. Staels B. J. Clin. Endocrinol. Metab. 2007; 92: 386-395Crossref PubMed Scopus (395) Google Scholar). Through these beneficial effects, TZDs offer a new type of oral therapy for type II diabetes by reducing insulin resistance and assisting glycemic control.Like adipocytes, many human cancer cell lines exhibit high levels of PPARγ expression. In vitro exposure of these tumor cells to high doses (≥50 μm) of troglitazone and ciglitazone led to cell cycle arrest, apoptosis, and redifferentiation (5.Grommes C. Landreth G.E. Heneka M.T. Lancet Oncol. 2004; 5: 419-429Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar, 6.Jiang M. Shappell S.B. Hayward S.W. J. Cell Biochem. 2004; 91: 513-527Crossref PubMed Scopus (30) Google Scholar, 7.Koeffler H.P. Clin. Cancer Res. 2003; 9: 1-9PubMed Google Scholar, 8.Kopelovich L. Fay J.R. Glazer R.I. Crowell J.A. Mol. Cancer Ther. 2002; 1: 357-363Crossref PubMed Scopus (17) Google Scholar, 9.Weng J.R. Chen C.Y. Pinzone J.J. Ringel M.D. Chen C.S. Endocr. Relat. Cancer. 2006; 13: 401-413Crossref PubMed Scopus (119) Google Scholar), suggesting a putative link between PPARγ signaling and the antitumor activities of TZDs. Furthermore, the in vivo anticancer efficacy of troglitazone was demonstrated in a few clinical cases that involved patients with liposarcomas or prostate cancer (10.Demetri G.D. Fletcher C.D. Mueller E. Sarraf P. Naujoks R. Campbell N. Spiegelman B.M. Singer S. Proc. Natl. Acad. Sci. U.S.A. 1999; 96: 3951-3956Crossref PubMed Scopus (462) Google Scholar, 11.Hisatake J.I. Ikezoe T. Carey M. Holden S. Tomoyasu S. Koeffler H.P. Cancer Res. 2000; 60: 5494-5498PubMed Google Scholar). Although the identities of target genes that contribute to the antiproliferative activities of PPARγ agonists remain elusive (7.Koeffler H.P. Clin. Cancer Res. 2003; 9: 1-9PubMed Google Scholar), accumulating evidence indicates that TZDs mediate PPARγ-independent antitumor effects by targeting diverse signaling pathways governing the proliferation and survival of cancer cells (12.Wei S. Yang J. Lee S.L. Kulp S.K. Chen C.S. Cancer Lett. 2009; 276: 119-124Crossref PubMed Scopus (91) Google Scholar). Of the various “off target” mechanisms identified, the effects of TZDs on the repression of diverse cell cycle- and apoptosis-regulatory proteins are especially noteworthy (13.Wei S. Lin L.F. Yang C.C. Wang Y.C. Chang G.D. Chen H. Chen C.S. Mol. Pharmacol. 2007; 72: 725-733Crossref PubMed Scopus (45) Google Scholar, 14.Yang C.C. Wang Y.C. Wei S. Lin L.F. Chen C.S. Lee C.C. Lin C.C. Chen C.S. Cancer Res. 2007; 67: 3229-3238Crossref PubMed Scopus (45) Google Scholar). We previously demonstrated that this effect was attributable to the ability of TZDs to activate β-transducin repeat-containing protein (β-TrCP)-mediated proteolysis of target proteins, including β-catenin, cyclin D1, and Sp1, by increasing the expression level of β-TrCP, a versatile F-box protein of the Skp1/Cul1/F-box ubiquitin ligase (13.Wei S. Lin L.F. Yang C.C. Wang Y.C. Chang G.D. Chen H. Chen C.S. Mol. Pharmacol. 2007; 72: 725-733Crossref PubMed Scopus (45) Google Scholar, 15.Wei S. Yang H.C. Chuang H.C. Yang J. Kulp S.K. Lu P.J. Lai M.D. Chen C.S. J. Biol. Chem. 2008; 283: 26759-26770Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 16.Wei S. Chuang H.C. Tsai W.C. Yang H.C. Ho S.R. Paterson A.J. Kulp S.K. Chen C.S. Mol. Pharmacol. 2009; 76: 47-57Crossref PubMed Scopus (41) Google Scholar). Furthermore, decreased Sp1 expression leads to the transcriptional repression of a series of genes involved in oncogenic transformation (16.Wei S. Chuang H.C. Tsai W.C. Yang H.C. Ho S.R. Paterson A.J. Kulp S.K. Chen C.S. Mol. Pharmacol. 2009; 76: 47-57Crossref PubMed Scopus (41) Google Scholar), including those encoding androgen receptor (AR), estrogen receptor α (ERα), and epidermal growth factor receptor (see Fig. 1A). In contrast, nonmalignant cells are resistant to these PPARγ-independent antitumor effects, underscoring the translational potential of TZDs to develop novel antitumor agents with a unique mode of mechanism. The proof-of-principle of this premise was provided by two PPARγ-inactive derivatives, STG28 and OSU-CG12, which exhibit multifold higher antitumor potencies than the respective parent compounds, troglitazone and ciglitazone, while lacking the ability to transactivate PPARγ (17.Huang J.W. Shiau C.W. Yang J. Wang D.S. Chiu H.C. Chen C.Y. Chen C.S. J. Med. Chem. 2006; 49: 4684-4689Crossref PubMed Scopus (51) Google Scholar, 18.Yang J. Wei S. Wang D.S. Wang Y.C. Kulp S.K. Chen C.S. J. Med. Chem. 2008; 51: 2100-2107Crossref PubMed Scopus (25) Google Scholar) (see Fig. 1A).In the course of our investigation of the mechanism underlying TZD-induced activation of β-TrCP signaling, we observed that this β-TrCP-mediated proteolysis also occurred under conditions of glucose deprivation (15.Wei S. Yang H.C. Chuang H.C. Yang J. Kulp S.K. Lu P.J. Lai M.D. Chen C.S. J. Biol. Chem. 2008; 283: 26759-26770Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 16.Wei S. Chuang H.C. Tsai W.C. Yang H.C. Ho S.R. Paterson A.J. Kulp S.K. Chen C.S. Mol. Pharmacol. 2009; 76: 47-57Crossref PubMed Scopus (41) Google Scholar), raising the possibility that TZDs act by mimicking energy restriction. Here, we demonstrate that troglitazone, ciglitazone, STG28, and OSU-CG12 were able to elicit hallmark cellular responses characteristic of energy restriction in LNCaP prostate cancer and MCF-7 breast cancer cells, paralleling those induced by glucose starvation and two known energy restriction-mimetic agents (ERMAs), 2-deoxyglucose (2-DG), and resveratrol (19.Baur J.A. Sinclair D.A. Nat. Rev. Drug Discov. 2006; 5: 493-506Crossref PubMed Scopus (3163) Google Scholar, 20.Cucciolla V. Borriello A. Oliva A. Galletti P. Zappia V. Della Ragione F. Cell Cycle. 2007; 6: 2495-2510Crossref PubMed Scopus (143) Google Scholar, 21.Bishayee A. Cancer Prev. Res. 2009; 2: 409-418Crossref PubMed Scopus (432) Google Scholar). These changes include reduced glycolytic rate, transient induction of the NAD+-dependent histone deacetylase Sirt1 (silent information regulator 1) (22.Cohen H.Y. Miller C. Bitterman K.J. Wall N.R. Hekking B. Kessler B. Howitz K.T. Gorospe M. de Cabo R. Sinclair D.A. Science. 2004; 305: 390-392Crossref PubMed Scopus (1657) Google Scholar), and activation of the intracellular fuel sensor AMP-activated protein kinase (AMPK) (23.Jiang W. Zhu Z. Thompson H.J. Cancer Res. 2008; 68: 5492-5499Crossref PubMed Scopus (140) Google Scholar) and ER stress (24.Lin A.Y. Lee A.S. Proc. Natl. Acad. Sci. U.S.A. 1984; 81: 988-992Crossref PubMed Scopus (57) Google Scholar, 25.Lee A.S. Trends Biochem. Sci. 2001; 26: 504-510Abstract Full Text Full Text PDF PubMed Scopus (918) Google Scholar), the interplay among which culminates in autophagy and apoptosis. This study provides the first evidence that β-TrCP-dependent proteolysis represents a downstream cellular event of transient Sirt1 induction, which underlies the effect of energy restriction on apoptosis induction.DISCUSSIONCancer cells gain growth advantages in the microenvironment by shifting cellular metabolism to aerobic glycolysis, the so-called Warburg effect (52.Gatenby R.A. Gillies R.J. Nat. Rev. Cancer. 2004; 4: 891-899Crossref PubMed Scopus (3611) Google Scholar, 53.Kim J.W. Dang C.V. Cancer Res. 2006; 66: 8927-8930Crossref PubMed Scopus (979) Google Scholar, 54.Samudio I. Fiegl M. Andreeff M. Cancer Res. 2009; 69: 2163-2166Crossref PubMed Scopus (235) Google Scholar). There is a growing interest in targeting aerobic glycolysis for cancer therapy by exploiting the differential susceptibility of malignant versus normal cells to glycolytic inhibition (55.Chen Z. Lu W. Garcia-Prieto C. Huang P. J. Bioenerg. Biomembr. 2007; 39: 267-274Crossref PubMed Scopus (257) Google Scholar), of which the proof-of-concept is provided by the in vivo efficacy of dietary caloric restriction (23.Jiang W. Zhu Z. Thompson H.J. Cancer Res. 2008; 68: 5492-5499Crossref PubMed Scopus (140) Google Scholar, 56.Hursting S.D. Lavigne J.A. Berrigan D. Perkins S.N. Barrett J.C. Annu. Rev. Med. 2003; 54: 131-152Crossref PubMed Scopus (467) Google Scholar, 57.Thompson H.J. Zhu Z. Jiang W. J. Mammary Gland Biol. Neoplasia. 2003; 8: 133-142Crossref PubMed Scopus (49) Google Scholar, 58.Berrigan D. Perkins S.N. Haines D.C. Hursting S.D. Carcinogenesis. 2002; 23: 817-822Crossref PubMed Scopus (168) Google Scholar), resveratrol (19.Baur J.A. Sinclair D.A. Nat. Rev. Drug Discov. 2006; 5: 493-506Crossref PubMed Scopus (3163) Google Scholar, 20.Cucciolla V. Borriello A. Oliva A. Galletti P. Zappia V. Della Ragione F. Cell Cycle. 2007; 6: 2495-2510Crossref PubMed Scopus (143) Google Scholar), and 2-DG (59.Zhu Z. Jiang W. McGinley J.N. Thompson H.J. Cancer Res. 2005; 65: 7023-7030Crossref PubMed Scopus (113) Google Scholar) in suppressing carcinogenesis in various spontaneous or chemical-induced tumor animal models. Because chronic energy restriction proves to be difficult to implement as a chemopreventive strategy, 2-DG and resveratrol have received wide attention because of their abilities to mimic the beneficial effects of energy restriction by inhibiting glucose metabolism and uptake, respectively (19.Baur J.A. Sinclair D.A. Nat. Rev. Drug Discov. 2006; 5: 493-506Crossref PubMed Scopus (3163) Google Scholar, 20.Cucciolla V. Borriello A. Oliva A. Galletti P. Zappia V. Della Ragione F. Cell Cycle. 2007; 6: 2495-2510Crossref PubMed Scopus (143) Google Scholar, 59.Zhu Z. Jiang W. McGinley J.N. Thompson H.J. Cancer Res. 2005; 65: 7023-7030Crossref PubMed Scopus (113) Google Scholar). However, as indicated by our data, 2-DG and resveratrol require at least 1 mm and 100 μm, respectively, to attain antitumor activities. Thus, the relatively weak in vitro potencies of these agents limit their therapeutic applications.Here, we demonstrate that TZDs represent a novel class of ERMAs in that they elicit hallmark cellular responses characteristic of energy restriction in a manner reminiscent of that of resveratrol and 2-DG. OSU-CG12 mimicked the effect of energy restriction, as manifested by a reduced glycolytic rate and decreased NADH and lactate production. This drug-induced metabolic deficiency signaled the induction of key starvation-associated responses, including transient Sirt 1 induction, AMPK activation, and ER stress, each of which mediates a distinct signaling pathway culminating in the antiproliferative effects of OSU-CG12 (Fig. 9C). Moreover, these energy restriction-associated responses could be achieved at concentrations in the 5 μm range relative to 100 μm and 5 mm for resveratrol and 2-DG, respectively, indicating that the development of potent ERMAs from the molecular scaffold of TZDs is feasible. From a translational perspective, the development of novel ERMAs with greater antitumor potencies may provide advantages in clinical development.Several lines of evidence suggest that OSU-CG12-mediated inhibition of glucose metabolism might be attributable to the cumulative effect of a series of biochemical events at different stages of drug action, including the immediate responses of reduced glucose uptake and inhibition of mTOR-p70S6K signaling, followed by Akt inactivation and eIF2α phosphorylation. Thus, OSU-CG12 inhibits glucose metabolism through effects at different molecular levels, including the cellular uptake of glucose and the transcription of genes associated with glycolysis and energy metabolism. Further investigation of additional mechanisms is currently underway.Previous studies have implicated AMPK activation and ER stress as targets for selective cancer cell killing during calorie restriction (23.Jiang W. Zhu Z. Thompson H.J. Cancer Res. 2008; 68: 5492-5499Crossref PubMed Scopus (140) Google Scholar, 60.Saito S. Furuno A. Sakurai J. Sakamoto A. Park H.R. Shin-Ya K. Tsuruo T. Tomida A. Cancer Res. 2009; 69: 4225-4234Crossref PubMed Scopus (131) Google Scholar). However, the role of Sirt1 in regulating cell death response is less well defined considering its controversial role as a tumor promoter or tumor suppressor (61.Deng C.X. Int. J. Biol. Sci. 2009; 5: 147-152Crossref PubMed Scopus (266) Google Scholar). Sirt1 is able to regulate epigenetic changes as well as the functions of a broad spectrum of nonhistone signaling proteins via deacetylation (62.Anastasiou D. Krek W. Physiology. 2006; 21: 404-410Crossref PubMed Scopus (82) Google Scholar). Here, we provide the first evidence that the transient increase in Sirt1 expression plays a crucial role in mediating the induction of apoptosis by ERMAs through the activation of β-TrCP-facilitated proteolysis. It is noteworthy that the Sirt1-mediated up-regulation of β-TrCP expression was achieved through protein stabilization, for which Sirt1 deacetylase activity was critical. This stabilization of β-TrCP protein might be attributable to the ability of Sirt1 to suppress the expression/activity of a specific E3 ligase that targets β-TrCP for proteasome-mediated proteolysis, which is currently under investigation. Moreover, although AMPK has been reported to enhance Sirt1 activity by increasing intracellular NAD+ levels (63.Cantó C. Gerhart-Hines Z. Feige J.N. Lagouge M. Noriega L. Milne J.C. Elliott P.J. Puigserver P. Auwerx J. Nature. 2009; 458: 1056-1060Crossref PubMed Scopus (2268) Google Scholar), our data indicate that neither genetic nor pharmacological inhibition of AMPK had any effect on β-TrCP expression in TZD-treated cancer cells, suggesting that AMPK activation did not play a role in β-TrCP protein stabilization. Although substantial evidence indicates the importance of autophagy in cancer, its role in modulating therapeutic response, by either enhancing or protecting cells from drug-induced cell death, remains unclear (50.Kondo Y. Kanzawa T. Sawaya R. Kondo S. Nat. Rev. Cancer. 2005; 5: 726-734Crossref PubMed Scopus (1451) Google Scholar, 51.Tsuchihara K. Fujii S. Esumi H. Cancer Lett. 2009; 278: 130-138Crossref PubMed Scopus (96) Google Scholar). In the case of ERMAs, our data suggest that the interplay between autophagy and apoptosis plays a key role in mediating their antiproliferative activities. IntroductionThiazolidinediones (TZDs) 2The abbreviations used are: TZDthiazolidinedioneERMAenergy restriction-mimetic agentPPARperoxisome proliferator-activated receptorTrCPtransducin repeat-containing proteinARandrogen receptorERestrogen receptor2-DG2-deoxyglucoseAMPKAMP-activated protein kinasePrECprostate epithelial cellGFPgreen fluorescent proteinPARPpoly(ADP-ribose) polymeraseERKextracellular signal-regulated kinasemTORmammalian homolog of target of rapamycinTSCtuberous sclerosis complexLClight chaineIFeukaryotic translation initiation factorAtgautophagy-related geneHAhemagglutininGADDgrowth arrest and DNA damage-inducible genesiRNAsmall interfering RNAshRNAsmall hairpin RNAWTwild typeRTreverse transcriptionPBSphosphate-buffered salineMTT3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)LDHlactate dehydrogenase. are selective ligands for the nuclear transcription factor peroxisome proliferator-activated receptor (PPAR) γ (1.Yki-Järvinen H. N. Engl. J. Med. 2004; 351: 1106-1118Crossref PubMed Scopus (1880) Google Scholar, 2.Panchapakesan U. Chen X.M. Pollock C.A. Nat. Clin. Pract. Nephrol. 2005; 1: 33-43Crossref PubMed Scopus (44) Google Scholar). These TZDs improve insulin sensitivity by transcriptional activation of insulin-sensitive genes involved in glucose homeostasis, fatty acid metabolism, and triacylglycerol storage in adipocytes and promote the differentiation of preadipocytes by mimicking the genomic effects of insulin (3.Olefsky J.M. J. Clin. Invest. 2000; 106: 467-472Crossref PubMed Scopus (504) Google Scholar, 4.Sharma A.M. Staels B. J. Clin. Endocrinol. Metab. 2007; 92: 386-395Crossref PubMed Scopus (395) Google Scholar). Moreover, TZD-mediated PPARγ activation has been shown to promote the differentiation of preadipocytes by mimicking the genomic effects of insulin on adipocytes and to modulate the expression of adiponectin, pro-inflammatory cytokines like interleukin-6 and tumor necrosis factor α and a host of endocrine regulators in adipocytes and macrophages (3.Olefsky J.M. J. Clin. Invest. 2000; 106: 467-472Crossref PubMed Scopus (504) Google Scholar, 4.Sharma A.M. Staels B. J. Clin. Endocrinol. Metab. 2007; 92: 386-395Crossref PubMed Scopus (395) Google Scholar). Through these beneficial effects, TZDs offer a new type of oral therapy for type II diabetes by reducing insulin resistance and assisting glycemic control.Like adipocytes, many human cancer cell lines exhibit high levels of PPARγ expression. In vitro exposure of these tumor cells to high doses (≥50 μm) of troglitazone and ciglitazone led to cell cycle arrest, apoptosis, and redifferentiation (5.Grommes C. Landreth G.E. Heneka M.T. Lancet Oncol. 2004; 5: 419-429Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar, 6.Jiang M. Shappell S.B. Hayward S.W. J. Cell Biochem. 2004; 91: 513-527Crossref PubMed Scopus (30) Google Scholar, 7.Koeffler H.P. Clin. Cancer Res. 2003; 9: 1-9PubMed Google Scholar, 8.Kopelovich L. Fay J.R. Glazer R.I. Crowell J.A. Mol. Cancer Ther. 2002; 1: 357-363Crossref PubMed Scopus (17) Google Scholar, 9.Weng J.R. Chen C.Y. Pinzone J.J. Ringel M.D. Chen C.S. Endocr. Relat. Cancer. 2006; 13: 401-413Crossref PubMed Scopus (119) Google Scholar), suggesting a putative link between PPARγ signaling and the antitumor activities of TZDs. Furthermore, the in vivo anticancer efficacy of troglitazone was demonstrated in a few clinical cases that involved patients with liposarcomas or prostate cancer (10.Demetri G.D. Fletcher C.D. Mueller E. Sarraf P. Naujoks R. Campbell N. Spiegelman B.M. Singer S. Proc. Natl. Acad. Sci. U.S.A. 1999; 96: 3951-3956Crossref PubMed Scopus (462) Google Scholar, 11.Hisatake J.I. Ikezoe T. Carey M. Holden S. Tomoyasu S. Koeffler H.P. Cancer Res. 2000; 60: 5494-5498PubMed Google Scholar). Although the identities of target genes that contribute to the antiproliferative activities of PPARγ agonists remain elusive (7.Koeffler H.P. Clin. Cancer Res. 2003; 9: 1-9PubMed Google Scholar), accumulating evidence indicates that TZDs mediate PPARγ-independent antitumor effects by targeting diverse signaling pathways governing the proliferation and survival of cancer cells (12.Wei S. Yang J. Lee S.L. Kulp S.K. Chen C.S. Cancer Lett. 2009; 276: 119-124Crossref PubMed Scopus (91) Google Scholar). Of the various “off target” mechanisms identified, the effects of TZDs on the repression of diverse cell cycle- and apoptosis-regulatory proteins are especially noteworthy (13.Wei S. Lin L.F. Yang C.C. Wang Y.C. Chang G.D. Chen H. Chen C.S. Mol. Pharmacol. 2007; 72: 725-733Crossref PubMed Scopus (45) Google Scholar, 14.Yang C.C. Wang Y.C. Wei S. Lin L.F. Chen C.S. Lee C.C. Lin C.C. Chen C.S. Cancer Res. 2007; 67: 3229-3238Crossref PubMed Scopus (45) Google Scholar). We previously demonstrated that this effect was attributable to the ability of TZDs to activate β-transducin repeat-containing protein (β-TrCP)-mediated proteolysis of target proteins, including β-catenin, cyclin D1, and Sp1, by increasing the expression level of β-TrCP, a versatile F-box protein of the Skp1/Cul1/F-box ubiquitin ligase (13.Wei S. Lin L.F. Yang C.C. Wang Y.C. Chang G.D. Chen H. Chen C.S. Mol. Pharmacol. 2007; 72: 725-733Crossref PubMed Scopus (45) Google Scholar, 15.Wei S. Yang H.C. Chuang H.C. Yang J. Kulp S.K. Lu P.J. Lai M.D. Chen C.S. J. Biol. Chem. 2008; 283: 26759-26770Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 16.Wei S. Chuang H.C. Tsai W.C. Yang H.C. Ho S.R. Paterson A.J. Kulp S.K. Chen C.S. Mol. Pharmacol. 2009; 76: 47-57Crossref PubMed Scopus (41) Google Scholar). Furthermore, decreased Sp1 expression leads to the transcriptional repression of a series of genes involved in oncogenic transformation (16.Wei S. Chuang H.C. Tsai W.C. Yang H.C. Ho S.R. Paterson A.J. Kulp S.K. Chen C.S. Mol. Pharmacol. 2009; 76: 47-57Crossref PubMed Scopus (41) Google Scholar), including those encoding androgen receptor (AR), estrogen receptor α (ERα), and epidermal growth factor receptor (see Fig. 1A). In contrast, nonmalignant cells are resistant to these PPARγ-independent antitumor effects, underscoring the translational potential of TZDs to develop novel antitumor agents with a unique mode of mechanism. The proof-of-principle of this premise was provided by two PPARγ-inactive derivatives, STG28 and OSU-CG12, which exhibit multifold higher antitumor potencies than the respective parent compounds, troglitazone and ciglitazone, while lacking the ability to transactivate PPARγ (17.Huang J.W. Shiau C.W. Yang J. Wang D.S. Chiu H.C. Chen C.Y. Chen C.S. J. Med. Chem. 2006; 49: 4684-4689Crossref PubMed Scopus (51) Google Scholar, 18.Yang J. Wei S. Wang D.S. Wang Y.C. Kulp S.K. Chen C.S. J. Med. Chem. 2008; 51: 2100-2107Crossref PubMed Scopus (25) Google Scholar) (see Fig. 1A).In the course of our investigation of the mechanism underlying TZD-induced activation of β-TrCP signaling, we observed that this β-TrCP-mediated proteolysis also occurred under conditions of glucose deprivation (15.Wei S. Yang H.C. Chuang H.C. Yang J. Kulp S.K. Lu P.J. Lai M.D. Chen C.S. J. Biol. Chem. 2008; 283: 26759-26770Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 16.Wei S. Chuang H.C. Tsai W.C. Yang H.C. Ho S.R. Paterson A.J. Kulp S.K. Chen C.S. Mol. Pharmacol. 2009; 76: 47-57Crossref PubMed Scopus (41) Google Scholar), raising the possibility that TZDs act by mimicking energy restriction. Here, we demonstrate that troglitazone, ciglitazone, STG28, and OSU-CG12 were able to elicit hallmark cellular responses characteristic of energy restriction in LNCaP prostate cancer and MCF-7 breast cancer cells, paralleling those induced by glucose starvation and two known energy restriction-mimetic agents (ERMAs), 2-deoxyglucose (2-DG), and resveratrol (19.Baur J.A. Sinclair D.A. Nat. Rev. Drug Discov. 2006; 5: 493-506Crossref PubMed Scopus (3163) Google Scholar, 20.Cucciolla V. Borriello A. Oliva A. Galletti P. Zappia V. Della Ragione F. Cell Cycle. 2007; 6: 2495-2510Crossref PubMed Scopus (143) Google Scholar, 21.Bishayee A. Cancer Prev. Res. 2009; 2: 409-418Crossref PubMed Scopus (432) Google Scholar). These changes include reduced glycolytic rate, transient induction of the NAD+-dependent histone deacetylase Sirt1 (silent information regulator 1) (22.Cohen H.Y. Miller C. Bitterman K.J. Wall N.R. Hekking B. Kessler B. Howitz K.T. Gorospe M. de Cabo R. Sinclair D.A. 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