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Suppressive Effects of Dehydroepiandrosterone and the Nuclear Factor-B Inhibitor Parthenolide on Corticotroph Tumor Cell Growth and Function in Vitro and in Vivo

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Suppressive Effects of Dehydroepiandrosterone and the Nuclear Factor-B Inhibitor Parthenolide on Corticotroph Tumor Cell Growth and Function in Vitro and in Vivo 321 Suppressive effects of dehydroepiandrosterone and the nuclear factor-B inhibitor parthenolide on corticotroph tumor cell growth and function in vitro and in vivo T Taguchi, T Takao, Y Iwasaki, M Nishiyama, K Asaba and K Hashimoto Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Oko-cho, Kohasu, Nankoku 783-8505, Japan (Requests for offprints should be addressed to T Taguchi; Email: [email protected]) Abstract Dehydroepiandrosterone (DHEA) is believed to have an xenografts of AtT20 cells in vivo, we found that the anti-tumor effect, as well as anti-inflammatory, antioxi- combined administration of DHEA and PRT significantly dant, and anti-aging effects. To clarify the possible inhibi- attenuated tumor growth and survivin expression. The tory action of DHEA on pituitary tumor cells, we tested treatment also decreased the elevated plasma corticoster- the effects of DHEA, alone or in combination with the one levels and ameliorated the malnutrition induced by nuclear factor-B (NF-B) inhibitor parthenolide (PRT), tumor growth. Altogether, these results suggested that on AtT20 corticotroph cell growth and function both combined treatments of DHEA and PRT potently inhibit in vitro and in vivo. We found that, in vitro, DHEA and PRT the growth and function of corticotroph tumor cells both had potent inhibitory effects on pro-opiomelanocortin in vitro and in vivo. This effect may, at least partly, be and NF-B-dependent gene expression. They also sup- caused by the suppressive effects of these compounds, such pressed the transcription activity of survivin, a represen- as survivin and other inhibitor of apoptosis proteins, on tative anti-apoptotic factor, and induced apoptosis in this NF-B-mediated gene transcription. cell line. Furthermore, using BALB/C nude mice with Journal of Endocrinology (2006) 188, 321–331 Introduction Dehydroepiandrosterone (DHEA) is an adrenal steroid which acts as a precursor of sex steroids such as androgen Adrenocorticotropin (ACTH)-dependent Cushing’s syn- and estrogen (Miller 2002). Besides its effects as a pro- drome, induced either by a corticotroph tumor in the hormone, DHEA itself is suggested to have a variety of pituitary or by an ectopic ACTH-producing tumor, is a beneficial effects such as anti-tumor, anti-diabetic, anti- life-threatening disease, causing metabolic derangements atherosclerotic, and anti-aging effects (Aoki et al. 2003). such as diabetes mellitus, hypertension, atherosclerosis, Some of these effects are thought to be mediated by its and immune dysfunction (Arnaldi et al. 2003). Although antioxidant properties via inhibition of nuclear factor-B surgical treatments are essential for the disorder, medical (NF-B) (Aragno et al. 2002, Iwasaki et al. 2004), which treatment is sometimes necessary in cases with incomplete is a transcription factor known to exert anti-apoptotic removal of the tumor, recurrence, or in cases unsuitable effects in neoplasia. DHEA is indeed reported to elicit for surgical procedure. Paez-Perada et al. (2001) showed cellular apoptosis in both tumor and non-tumor cells that retinoic acid, an inducer of cell differentiation, in vitro (Yang et al. 2000, Liang et al. 2004). Thus, it is has potent inhibitory effects on Cushing’s adenoma possible that, like TZD, DHEA may exert negative effects using AtT20 mouse corticotroph tumor cells as a model on corticotroph tumor cell growth and function by system. More recently, Heaney et al. (2002) reported the inhibiting the NF-B signaling pathway. effectiveness of thiazolidinedione (TZD), a peroxisome The fate of normal cells is determined by the regulation proliferator-activated receptor (PPAR)- agonist, on this of the apoptotic mechanism, a system of programmed cell disorder, again using the AtT20 cell xenograft. Although death controlling cellular survival. In contrast, this mech- the precise mechanism of the effect of TZD on the anism is known to be inhibited in tumor cells, by the pituitary tumor cell has not yet been clarified, recent expression of anti-apoptotic factors such as inhibitors of studies suggest that TZD acts as an inducer of apoptosis in apoptosis proteins (IAPs) (Ambrosini et al. 1997, Salvesen some other tissues (Lu et al. 2005, Shiau et al. 2005). & Duckett 2002, Schimmer 2004). Thus, induction of Journal of Endocrinology (2006) 188, 321–331 DOI: 10.1677/joe.1.06418 0022–0795/06/0188–321 2006 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/25/2021 07:08:57AM via free access 322 T TAGUCHI and others · Corticotroph tumor suppression by DHEA/parthenolide apoptosis by targeting these proteins is expected to be 5% CO2–95% air atmosphere at 37 C. For each experi- applicable for clinical cancer therapy (LaCasse et al. 1998). ment, cells were plated in 24-well culture dishes with Although various IAPs are known to be expressed in approximately 70% confluence. For transient transfection tumor cells, some studies suggest that many of these experiments, AtT20 cells were transfected with a variety factors, including survivin (Ambrosini et al. 1997, Swana of reporter plasmids using the lipofection method. et al. 1999), a representative IAP, are induced by the activation of the NF-B pathway (LaCasse et al. 1998, Kawakami et al. 2005). Specific inhibition of this tran- Cell culture experiments scription factor is shown to induce apoptosis (Umezawa & On the day of the experiment, stock solutions of test Chaicharoenpong 2002, Horiguchi et al. 2003). In this substances (DHEA, E2, PRT, and testosterone) were regard, a sesquiterpene lactone, parthenolide (PRT), may added directly to the serum-free culture medium of each be an appropriate candidate, because it exerts a potent dish, and the cells were incubated for 24 h. At the end of ff inhibitory e ect on the NF-B pathway with low each experiment, the culture media were removed, and ff toxicity. The e ectiveness of this compound has already the cells were harvested using lysis buffer. Luciferase assay been shown for a variety of human tumor cells (Nakshatri for determining the promoter activity of POMC, sur- ff et al. 2004). Furthermore, it is more e ective when used vivin, and NF-B–luciferase was performed using a in combination with conventional chemotherapy and luciferase assay system (Promega) according to the manu- radiotherapy (Patel et al. 2000, Riggins et al. 2005). facturer’s instructions. ACTH secreted into the culture ff In this study, we have examined the e ects of DHEA medium was measured by immunoradiometric assay and PRT on ACTH-secreting pituitary tumors applying (ACTH immunoradiometric assay kit; Mitsubishi an in vitro and in vivo experimental model system pre- Chemical, Tokyo, Japan). viously used for the examination of medical therapy for Cushing’s disease (Heaney et al. 2002). Because DHEA and PRT are not toxic in vivo, and both are known to have RT-PCR apoptosis-inducing as well as anti-NF-B properties, we expected the combination of these reagents to have a RNA was isolated using TRIZOL reagent (Invitrogen), more significant effect. Indeed, we found in this study that and 2 µg of the total RNA was used for the RT reaction DHEA and PRT, either alone or in combination, inhib- by Superscript III reverse transcriptase (Invitrogen). The ited corticotroph cell function in vitro, and that admin- cDNAs obtained were then amplified by PCR with Taq istration of both DHEA and PRT significantly attenuated DNA polymerase (Takara Shuzo, Kyoto, Japan). The the tumor growth in vivo. We also found that the sequences of primer sets for amplifying mouse IAPs were as follows: survivin forward, 5-GCGGAGGCTG treatment significantly reduced the expression of IAPs such as survivin and NF-B-dependent transcription. GCTTCA-3 , reverse, 5 -CTTGGCTCTCTGTCTGT CCA-3; mouse neuronal apoptosis inhibitory protein (mNAIP) forward, 5-ACATCACCACGTGTACTC TCA-3, reverse, 5-GGCTTCTGGAAGTGCACA Materials and Methods GTG-3; Bruce forward, 5-GATCTTGTTGCTAGAC ACTGC-3, reverse, 5-GGTCTCCCTTCTGTTAGC Materials TTC-3; X-linked inhibitor of apoptosis (XIAP) forward, NF-B–luciferase reporter plasmid was purchased from 5-GCAATGTTTCAGTTGTCATGCG-3, reverse, Stratagene (La Jolla, CA, USA). DHEA was obtained 5-CCAGCACTAGCTAACTCTCTG-3; inhibitor of from Wako Pure Chemicals (Osaka, Japan) and 17- apoptosis protein 1 (IAP1) forward, 5-GACAAGGTCA estradiol (E2), testosterone, and PRT were from Sigma AGTGCTTCTGC-3 , reverse, 5 -CTTACGTTCCCA Chemical Co. GTTGCTCAG-3; inhibitor of apoptosis protein 2 (IAP2) forward, 5-GTGTGAACTCTACCGAATGTC-3, reverse, 5-CTGCGGTGCTCTGACATAGC-3. Cultivation and transfection AtT20/D16 v mouse corticotroph tumor cells, or a Quantitative real-time RT-PCR stable transformant of the cell (AtT20PL) in which the rat pro-opiomelanocortin (POMC) gene 5-promoter RNA was isolated from liver and tumor tissues using (708 to +64; +1 indicates the transcription start site)– Sepasol-RNA1 Super (Nacalai Tesque Inc., Kyoto, Japan) luciferase fusion gene was stably incorporated, was used in according to the manufacturer’s instructions. cDNA was this study. Cells were maintained in a T75 culture flask synthesized from 2 µg RNA with Superscript III reverse with Dulbecco’s modified Eagles’ medium supplemented transcriptase in the presence of 1 µg random hexamer with 10% fetal bovine serum (Invitrogen) and antibiotics primers and 0·5 mM dNTPs (Promega). In survivin (50 U/ml penicillin and 50 µg/ml streptomycin) under a cDNA-specific quantitative RT-PCR assay, the reaction Journal of Endocrinology (2006) 188, 321–331 www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/25/2021 07:08:57AM via free access Corticotroph tumor suppression by DHEA/parthenolide · T TAGUCHI and others 323 mixture contained 10 µM survivin-forward and 10 µM Immunocytochemistry survivin-reverse primers, 10 µM TaqMan probe, 12·5 µl AtT20 cells (5103 cells/well) were plated on two-well TaqMan Universal PCR Master Mix (Applied Biosystems, chamber culture slides and treated with DHEA (100 µM) O, and 2 µl cDNA, in a total Foster City, CA, USA), H2 for 24 h.
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