TG-interacting factor transcriptionally induced by AKT/FOXO3A is a negative regulator that antagonizes arsenic trioxide-induced cancer cell apoptosis
Introduction
Arsenic has been used in traditional Chinese medicine (TCM) for the treatment of syphilis, ulcers and psoriasis for over two millennia. In 2000, arsenic trioxide (As2O3, ATO) was approved by the Food and Drug Administration (FDA) as a first-line chemotherapeutic agent for the treatment of both de novo and relapsed acute promyelocytic leukemia (APL) (Dilda and Hogg, 2007, Hughes et al., 2011). Furthermore, clinical trials of other arsenical-based cancer drugs are being conducted for the treatment of various forms of cancer, including: multiple myeloma (MM), myelodysplasia (MDS) and some solid tumors (Dilda and Hogg, 2007).
However, patients with hepatocellular carcinoma (HCC) who were treated with ATO, used as a single-agent in a phase II clinical trial, showed resistance to the treatment (Lin et al., 2007). In addition, chronic exposure to low-concentrations of (< 1 mg/kg) ATO in a mouse model of HCC can enhance tumor growth, angiogenesis and metastasis, but cannot induce tumor cell apoptosis (Liu et al., 2006). Furthermore, dual effects of ATO on APL cells were also found: inducing differentiation at low concentrations (0.1–0.5 μM) and apoptosis at high concentrations (0.5–2 μM) (Chen et al., 1997). Some dermatological diseases have been attributed to the long-term use of arsenic-based Fowler's solution (1% potassium arsenite) which was used successfully in the treatment of psoriasis, an inflammatory skin disease characterized by excessive proliferation of keratinocytes (Cuzick et al., 1982). Due to its toxic effects on patients, the medication was eventually prohibited from medical use (Hughes et al., 2011). Therefore, we suggest that ATO is a multi-target drug that has remarkable efficacy in the treatment of some diseases; however, its adverse effects should be particularly monitored, and fully elucidated so as to enhance its therapeutic utility.
In our previous studies, 20 μM ATO induced the ERK pathway to enhance cyclin-dependent kinase inhibitor CDKN1A expression and cellular apoptosis (Liu and Huang, 2008a). In contrast, ATO also activated the JNK pathway to phosphorylate c-Jun to recruit TG-interacting factor (TGIF)/HDAC1 complex to inhibit the CDKN1A promoter and result in apoptosis (Huang et al., 2006, Liu and Huang, 2008b, Huang et al., 2010). TGIF belongs to the TALE (three-amino-acid loop extension) subfamily of atypical homeodomain proteins (Bertolino et al., 1995), which plays a transcriptional repressor/co-repressor to modulate TGF-β (Wotton et al., 2001) and retinoic acid signaling (Bartholin et al., 2006). It has been implicated in diverse biological and pathological functions, such as: brain development (Gripp et al., 2000), hematopoietic stem cell function (Yan et al., 2013), regulating vascularization of the embryonic placenta (Bartholin et al., 2008), differentiation of preadipocytes (Horie et al., 2008) and various types of human cancer, such as: leukemia, ovarian cancer, liver cancer and gastric carcinoma (Imoto et al., 2000, Borlak et al., 2005, Hu et al., 2005, Hamid and Brandt, 2009). Recently, we also demonstrated that increased TGIF expression in upper-tract urothelial carcinoma (UTUC) patients after radical nephroureterectomy is associated with progression of the disease and worsened prognosis (Huang et al., 2012, Yeh et al., 2012). However, to date, evidence for the regulation of TGIF is limited.
In the present studies, ATO was found to have biphasic effects on various cancer cells, depending low or high concentrations. In particular, TGIF was involved in low-concentration (0.1–0.2 μM) ATO-induced cellular proliferation, migration, and invasion. Furthermore, the antagonistic effects of TGIF on high-concentration ATO-induced cell apoptosis were explored.
Section snippets
Reagents and antibodies
ATO, actinomycin D, LY294002, protein A-agarose beads and streptavidin-agarose were purchased from Sigma-Aldrich. The Wizard Plus MiniPrep DNA purification system, luciferase plasmid pGL-3 and the luciferase assay system were obtained from Promega. PD153035 and PP1 were purchased from Calbiochem. Lipofectamine™ 2000 reagent, the TRIzol® RNA extraction kit, SuperScript™ III, Dulbecco's modified Eagle's medium (DMEM) and Opti-MEM were obtained from Invitrogen. Antibodies against TGIF, CDKN1A,
TGIF mediates low-concentration ATO-induced cancer cell proliferation
According to our previous findings, there are opposing effects of ATO on A431 cells (Huang et al., 2006, Liu and Huang, 2008b, Huang et al., 2010), which might depend on the concentrations of ATO. To evaluate the effects of different concentrations of ATO on cellular responses, A431 cells were treated with various concentrations of ATO to measure their viability. Treatment with low-concentration (0.1 and 0.5 μM) ATO for 48 h increases cellular growth by about 10%, but with high-concentration (> 5
Discussion
As described above, ATO has been approved by the FDA as an effective chemotherapeutic agent for the treatment of patients with both de novo and relapsed APL (Dilda and Hogg, 2007, Hughes et al., 2011). Furthermore, several arsenical-based drugs are undergoing trials for the treatment of patients with other hematological malignancies and solid tumors (Dilda and Hogg, 2007); however, using ATO as a single-agent in a phase II clinical trial of patients with HCC indicates resistance to this
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgments
This work was supported by grants from the National Science Council (Taipei, Taiwan; NSC98-2320-B-006-008-MY3; NSC101-2320-B-006-034; NSC102-2320-B-006-017), and by a grant from Health and Welfare surcharge of tobacco products, Ministry of Health and Welfare (MOHW103-TD-B-111-05).
References (58)
- et al.
Maternal Tgif is required for vascularization of the embryonic placenta
Dev. Biol.
(2008) - et al.
A novel homeobox protein which recognizes a TGT core and functionally interferes with a retinoid-responsive motif
J. Biol. Chem.
(1995) - et al.
Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells
Blood
(1997) - et al.
Regulation of Akt/PKB activation by tyrosine phosphorylation
J. Biol. Chem.
(2001) - et al.
Arsenical-based cancer drugs
Cancer Treat. Rev.
(2007) - et al.
Arsenic trioxide — an old drug rediscovered
Blood Rev.
(2010) - et al.
Transforming growth-interacting factor (TGIF) regulates proliferation and differentiation of human myeloid leukemia cells
Mol. Oncol.
(2009) - et al.
Biphasic effect of arsenite on cell proliferation and apoptosis is associated with the activation of JNK and ERK1/2 in human embryo lung fibroblast cells
Toxicol. Appl. Pharmacol.
(2007) - et al.
TG-interacting factor is required for the differentiation of preadipocytes
J. Lipid Res.
(2008) - et al.
Involvement of reactive oxygen species in arsenite-induced downregulation of phospholipid hydroperoxide glutathione peroxidase in human epidermoid carcinoma A431 cells
Free Radic. Biol. Med.
(2002)