PPARgamma Inhibitors As Novel Tubulin-Targeting Agents

Overview

Journal PPAR Res

Publisher Wiley

Date 2008 May 30

PMID 18509498

Citations 10

Authors

Katherine L Schaefer

Affiliations

Soon will be listed here.

Abstract

The microtubule-targeting agents (MTAs) are a very successful class of cancer drugs with therapeutic benefits in both hematopoietic and solid tumors. However, resistance to these drugs is a significant problem. Current MTAs bind to microtubules, and/or to their constituent tubulin heterodimers, and affect microtubule polymerization and dynamics. The PPARgamma inhibitor T0070907 can reduce tubulin levels in colorectal cancer cell lines and suppress tumor growth in a murine xenograft model. T0070907 does not alter microtubule polymerization in vitro, and does not appear to work by triggering modulation of tubulin RNA levels subsequent to decreased polymerization. This observation suggests the possible development of antimicrotubule drugs that work by a novel mechanism, and implies the presence of cancer therapeutic targets that have not yet been exploited. This review summarizes what is known about PPARgamma inhibitors and cancer cell death, with emphasis on the tubulin phenotype and PPAR-dependence, and identifies potential mechanisms of action.

Citing Articles

Role of Ciminalum-4-thiazolidinone Hybrids in Molecular NF-κB Dependent Pathways.

Szlachcikowska D, Tabecka-Lonczynska A, Holota S, Roman O, Shepeta Y, Lesyk R Int J Mol Sci. 2024; 25(13).

PMID: 39000436 PMC: 11242080. DOI: 10.3390/ijms25137329.

Antiproliferative and Pro-Apoptotic Activity and Tubulin Dynamics Modulation of 1-Benzimidazol-2-yl Hydrazones in Human Breast Cancer Cell Line MDA-MB-231.

Yancheva D, Argirova M, Georgieva I, Milanova V, Guncheva M, Rangelov M Molecules. 2024; 29(10).

PMID: 38792260 PMC: 11123699. DOI: 10.3390/molecules29102400.

Evaluating the Therapeutic Potential of Curcumin and Synthetic Derivatives: A Computational Approach to Anti-Obesity Treatments.

Moetlediwa M, Jack B, Mazibuko-Mbeje S, Pheiffer C, Titinchi S, Salifu E Int J Mol Sci. 2024; 25(5).

PMID: 38473849 PMC: 10932351. DOI: 10.3390/ijms25052603.

Tubulin couples death receptor 5 to regulate apoptosis.

Twomey J, Zhao L, Luo S, Xu Q, Zhang B Oncotarget. 2019; 9(95):36804-36815.

PMID: 30613368 PMC: 6298406. DOI: 10.18632/oncotarget.26407.

A possible regulatory link between Twist 1 and PPARγ gene regulation in 3T3-L1 adipocytes.

Ren R, Chen Z, Zhao X, Sun T, Zhang Y, Chen J Lipids Health Dis. 2016; 15(1):189.

PMID: 27825360 PMC: 5101646. DOI: 10.1186/s12944-016-0361-x.

References

Pascual G, Fong A, Ogawa S, Gamliel A, Li A, Perissi V . A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005; 437(7059):759-63. PMC: 1464798. DOI: 10.1038/nature03988. View

Kopito R . Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 2000; 10(12):524-30. DOI: 10.1016/s0962-8924(00)01852-3. View

Powers M, Workman P . Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors. Endocr Relat Cancer. 2007; 13 Suppl 1:S125-35. DOI: 10.1677/erc.1.01324. View

Stirling P, Cuellar J, Alfaro G, El Khadali F, Beh C, Valpuesta J . PhLP3 modulates CCT-mediated actin and tubulin folding via ternary complexes with substrates. J Biol Chem. 2006; 281(11):7012-21. DOI: 10.1074/jbc.M513235200. View

Panigrahy D, Huang S, Kieran M, Kaipainen A . PPARgamma as a therapeutic target for tumor angiogenesis and metastasis. Cancer Biol Ther. 2005; 4(7):687-93. DOI: 10.4161/cbt.4.7.2014. View

Bishop-Bailey D, Hla T, Warner T . Bisphenol A diglycidyl ether (BADGE) is a PPARgamma agonist in an ECV304 cell line. Br J Pharmacol. 2000; 131(4):651-4. PMC: 1572386. DOI: 10.1038/sj.bjp.0703628. View

Esteve M, Carre M, Braguer D . Microtubules in apoptosis induction: are they necessary?. Curr Cancer Drug Targets. 2008; 7(8):713-29. DOI: 10.2174/156800907783220480. View

Bhalla K . Microtubule-targeted anticancer agents and apoptosis. Oncogene. 2003; 22(56):9075-86. DOI: 10.1038/sj.onc.1207233. View

Seargent J, Yates E, Gill J . GW9662, a potent antagonist of PPARgamma, inhibits growth of breast tumour cells and promotes the anticancer effects of the PPARgamma agonist rosiglitazone, independently of PPARgamma activation. Br J Pharmacol. 2004; 143(8):933-7. PMC: 1575954. DOI: 10.1038/sj.bjp.0705973. View

10.

Keller C, Lauring B . Possible regulation of microtubules through destabilization of tubulin. Trends Cell Biol. 2005; 15(11):571-3. DOI: 10.1016/j.tcb.2005.09.008. View

11.

Pasquier E, Andre N, Braguer D . Targeting microtubules to inhibit angiogenesis and disrupt tumour vasculature: implications for cancer treatment. Curr Cancer Drug Targets. 2007; 7(6):566-81. DOI: 10.2174/156800907781662266. View

12.

Zelnak A . Clinical pharmacology and use of microtubule-targeting agents in cancer therapy. Methods Mol Med. 2007; 137:209-34. DOI: 10.1007/978-1-59745-442-1_15. View

13.

Seiden-Long I, Brown K, Shih W, Wigle D, Radulovich N, Jurisica I . Transcriptional targets of hepatocyte growth factor signaling and Ki-ras oncogene activation in colorectal cancer. Oncogene. 2005; 25(1):91-102. DOI: 10.1038/sj.onc.1209005. View

14.

Yen T, Machlin P, Cleveland D . Autoregulated instability of beta-tubulin mRNAs by recognition of the nascent amino terminus of beta-tubulin. Nature. 1988; 334(6183):580-5. DOI: 10.1038/334580a0. View

15.

Maccioni R, Cambiazo V . Role of microtubule-associated proteins in the control of microtubule assembly. Physiol Rev. 1995; 75(4):835-64. DOI: 10.1152/physrev.1995.75.4.835. View

16.

Mooney D, Hansen L, Langer R, Vacanti J, Ingber D . Extracellular matrix controls tubulin monomer levels in hepatocytes by regulating protein turnover. Mol Biol Cell. 1994; 5(12):1281-8. PMC: 301157. DOI: 10.1091/mbc.5.12.1281. View

17.

Schaefer K, Wada K, Takahashi H, Matsuhashi N, Ohnishi S, Wolfe M . Peroxisome proliferator-activated receptor gamma inhibition prevents adhesion to the extracellular matrix and induces anoikis in hepatocellular carcinoma cells. Cancer Res. 2005; 65(6):2251-9. DOI: 10.1158/0008-5472.CAN-04-3037. View

18.

Hontecillas R, Bassaganya-Riera J . Peroxisome proliferator-activated receptor gamma is required for regulatory CD4+ T cell-mediated protection against colitis. J Immunol. 2007; 178(5):2940-9. DOI: 10.4049/jimmunol.178.5.2940. View

19.

Pasquier E, Honore S, Braguer D . Microtubule-targeting agents in angiogenesis: where do we stand?. Drug Resist Updat. 2006; 9(1-2):74-86. DOI: 10.1016/j.drup.2006.04.003. View

20.

Schaefer K, Takahashi H, Morales V, Harris G, Barton S, Osawa E . PPARgamma inhibitors reduce tubulin protein levels by a PPARgamma, PPARdelta and proteasome-independent mechanism, resulting in cell cycle arrest, apoptosis and reduced metastasis of colorectal carcinoma cells. Int J Cancer. 2006; 120(3):702-13. DOI: 10.1002/ijc.22361. View