EGFR Signaling and the Anti- Cancer Effects of Thiazolinedinediones Jesse Roman1

Moving away from PPARs - EGFR signaling and the anti- cancer effects of thiazolinedinediones Jesse Roman1

1Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, and Veterans Affairs Medical Center, Atlanta, Georgia 30322, USA Cell Research (2009) 19:669-671. doi: 10.1038/cr.2009.62; published online 1 June 2009

It is estimated that there were over 12 revealed that the use of thiazolidin- rest [4]. However, several investigators million new cases of cancer worldwide ediones was associated with reduced have found that thiazolidinediones have in 2007. Of these, lung cancer remains risk of lung cancer [3]. These studies cellular effects that are independent the number one cause of cancer death suggest that elucidating the mechanisms of PPARγ activation. In fact, thiazoli- in the U.S. and many other countries. responsible for the anti-cancer effects dinediones have been shown to in- Current therapy for lung cancer involves of thiazolidinediones might inform our hibit tumor growth in mice injected with multimodality therapies. Unfortunately, efforts for the development of new anti- PPARγ-deficient embryonic stem cells many patients are or become refractory cancer strategies. [5]. These so called PPARγ-independent to therapy and develop drug resistance. The thiazolidinediones are a class effects of thiazolidinediones include Kras and epidermal growth factor of antidiabetic drugs that includes induction of apoptosis by inhibition receptor (EGFR) mutations represent pioglitazone, rosiglitazone, ciglitazone, of the survival functions of Bcl-2/Bcl- some of the most common mutations and troglitazone. Earlier work revealed XL, effects on mitochondrial respira- in lung cancer and have been impli- that thiazolidinediones work by target- tory functions, inhibition of translation cated in chemoresistance. Therefore, ing peroxisome proliferator-activated initiation, and induction of tumor despite advances in the detection and receptors (PPAR) [4]. PPARs are ligand- suppressors [2, 4]. Thus, elucidating treatment of this disease, the overall activated transcription factors belonging the PPARγ-independent anti-cancer ef- 5-year survival rate remains less than to the nuclear hormone receptor super- fects of thiazolidinediones may prove 15% [1]. Advances in the management family that control energy homeostasis beneficial. of this deadly condition can come not and cell differentiation, proliferation, In a report published in this issue of only from strategies for early diagnosis, apoptosis, and inflammation. Early Cell Res, Li and colleagues showed that but also from new insights into disease research also linked PPARs to carcino- troglitazone inhibits the proliferation of pathogenesis that may lead to more ef- genesis and, to date, PPARs have been endothelial cells and several types of fective means of treatment. implicated in solid organ cancers like carcinoma cells through another PPARγ- The thiazolidinediones represent an breast, ovary, prostate, bladder, gastric, independent pathway that entails the interesting group of agents with modest colon, and lung cancers. Among the inhibition of EGFR signaling [6]. This anti-cancer activity demonstrated both three subtypes (PPARα, PPARβ/δ, and study not only adds to an increasing in vitro and in animal models [2]. Re- PPARγ), the role of PPAR-γ has been number of manuscripts exploring the cently, a retrospective analysis of data investigated the most in carcinogenesis anti-cancer effects of thiazolidiones, but obtained from the Veterans Integrated mainly because of the availability of also contributes to our understanding of Services Network 16 data warehouse thiazolidinediones, which are known to carcinogenesis in general, and dissects stimulate PPARγ effectively; this is the PPARγ-independent events responsible reason these agents are also referred to for this activity. Correspondence: Jesse Roman as PPARγ ligands. The choice of troglitazone for this Whitehead Biomedical Research Building, 615 By acting on PPARγ, thiazolidinedio- study is an interesting one considering Michael St, Suite 205-M, Atlanta, Georgia, 30322, USA nes inhibit tumor progression through that this drug was removed from the Tel: 404-712-2970; Fax: 404-712-2974 effects on cellular differentiation, market in 2000 because of hepatotoxic- E-mail: [email protected] apoptosis induction, and growth ar- ity. Despite this, its use in the laboratory www.cell-research.com | Cell Research npg 670 continues to unveil useful clues about pulmonary aorta endothelial cells, the cancer patients having mutated EGFR. cell cycle control and carcinogenesis. authors extended their work to carci- One wonders if these patients might The authors observed in porcine aorta noma cells, which allowed for a very in- benefit from therapies that include endothelial cells that troglitazone in- triguing observation; in essence, that not troglitazone. Yet, more information is duced the phosphorylation of Extracel- all carcinoma cells tested showed inhi- needed before strong conclusions are lular Signal-Regulated Kinases (Erk), bition of proliferation when exposed to drawn regarding its usefulness in the and used this system to explore the troglitazone. Specifically, A549 (a lung clinic. This is further highlighted by mechanisms responsible for the cellular epithelial cancer cell line) and Du145 several seemingly contradictory reports effects of troglitazone. Importantly, they (a prostate epithelial carcinoma cell showing that EGFR inhibitors may showed that troglitazone had the stron- line) cells showed decreased prolifera- protect against thiazalinedinedione- gest Erk inductive effect, while other tion, whereas Hela (cervical epithelial induced cell death in osteoblastic cells, thiazolidinediones (i.e., ciglitazone, carcinoma) and A431 (epidermoid car- that troglitazone induces EGFR trans- rosiglitazone and pioglitazone) had a cinoma) cells did not. Consistent with activation in certain cells, and that tro- lower effect with pioglitazone being their contention that EGFR mediated glitazone exerts its anti-cancer effects in the least efficient. Astutely, they noted the effects of troglitazone, inhibition breast cancer-derived cells not through that this ranking was different than that of cell growth was only demonstrated EGFR signaling, but mainly through expected if PPARγ was involved in the in cell lines that also showed increased alterations in the Na/H exchanger re- process, since earlier studies established EGFR degradation, but not in the ones sulting in intracellular acidosis [10]. a different predicted ranking order that did not. Clearly, thiazolidinediones have many for PPARγ-thiazolidinedione binding The observation that troglitazone effects other than PPARγ activation; the (Rosi > Pio > TGZ > Cig) [7]. They targets EGFR is an important one, par- elucidation of such mechanisms holds also showed that a chemical inhibitor ticularly in view of the role EGFR plays the promise of unveiling new targets of PPARγ and the transfection of cells in lung and other cancers. Interestingly, for the development of new anti-cancer with a dominant negative PPARγ DNA EGFR signaling has also been implicat- therapies. construct failed to inhibit the effects of ed in the cellular effects of rosiglitazone. troglitazone. Finally, they found that Furthermore, in A549 cells, rosigli- References troglitazone exerted similar effects in tazone potentiated the anti-proliferative 1 Spiro SG, Porter JC. Lung Cancer – LNCaP cells, which are deficient in effects of gefitinib, an EGFR inhibitor Where are we today? Current advances PPARγ. Together, these complementary available for clinical use in the treatment in staging and nonsurgical treatment. studies provide strong evidence that the of several cancers [8]. Am J Respir Crit Care Med 2002; phenomenon studied was independent Although a key message of this 166:1166-1196. of PPARγ activation. The studies also manuscript is that troglitazone can 2 Blanquicett C, Roman J, Hart CM. provide a good strategy for testing the exert anti-cancer effects independent Thiazolidinediones as anti-cancer role of PPARγ when defining intracel- of PPARγ activation, it is important to agents. Cancer Ther 2008; 6:25-34. 3 Govindarajan R, Ratnasinghe L, lular signals responsible for the effects note that PPARγ and EGFR signaling Simmons DL, et al. Thiazolidinediones of PPARγ ligands. appear to intersect in some cell types. and the risk of lung, prostate, and colon The group went on to show that tro- For example, in urothelium, PAPRγ cancer in patients with diabetes. J Clin glitazone binds to EGFR and induces regulation of urothelial differentiation Oncology 2007; 25:1476-1481. its internalization through Grb2, fol- is modulated by downstream EGFR 4 Roman J. Peroxisome proliferator- lowed by induction of Erks. Interest- signaling. This has led others to propose activated receptor gamma and lung ingly, Erk activation was not involved that a balance between PPARγ and cancer biology: implications for therapy. in troglitazone-induced cell growth EGFR signaling might be required for J Investig Med 2008; 56:528-533. 5 Palakurthi SS, Aktas H, Grubissich LM, inhibition; instead, regulation of Akt a cell to switch from differentiation to Mortensen RM, Halperin JA. Anticancer activation appeared important. The proliferation and vice versa [9]. effects of thiazolidinediones are authors concluded that troglitazone at- Together, the above observations sug- independent of peroxisome proliferator- tenuated overactive EGFR signaling by gest that troglitazone, through PPARγ- activated receptor gamma and mediated inhibition of Akt phosphorylation and independent signals that target EGFR, by inhibition of translation initiation. induction of effective endo-lysosomal might serve as a reasonable complement Cancer Res 2001; 61:6213-6218. degradation of the receptor leading to to current cancer therapeutic regimens. 6 Li X, Yang X, Xu Y, et al. Troglitazone inhibits cells proliferation by attenuation growth arrest. Interestingly, EGFR inhibitors such as of epidermal growth factor receptor Although many of the findings re- gefitinib show antitumor activity in only signaling independent of peroxisome ported by Li et al. were obtained using a subset (10-20%) of non-small cell lung proliferator-activated receptor γ. Cell

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