The Bcl-2/xL inhibitor ABT-263 increases the stability of Mcl-1 mRNA and protein in hepatocellular carcinoma cells
- Bin Wang†1,
- Zhenhong Ni†1,
- Xufang Dai2,
- Liyan Qin1,
- Xinzhe Li1,
- Liang Xu3,
- Jiqin Lian1Email author and
- Fengtian He1Email author
© Wang et al.; licensee BioMed Central Ltd. 2014
Received: 25 October 2013
Accepted: 24 April 2014
Published: 30 April 2014
Hepatocellular carcinoma (HCC) is one of the major causes of mortality. ABT-263 is a newly synthesized, orally available Bcl-2/xL inhibitor that shows promising efficacy in HCC therapy. ABT-263 inhibits the anti-apoptotic activity of Bcl-2 and Bcl-xL, but not Mcl-1. Previous reports have shown that ABT-263 upregulates Mcl-1 in various cancer cells, which contributes to ABT-263 resistance in cancer therapy. However, the associated mechanisms are not well known.
Western blot, RNAi and CCK-8 assays were used to investigate the relationship between Mcl-1 upregulation and ABT-263 sensitivity in HCC cells. Real-time PCR and Western blot were used to detect Mcl-1 mRNA and protein levels. Luciferase reporter assay and RNA synthesis inhibition assay were adopted to analyze the mechanism of Mcl-1 mRNA upregulation. Western blot and the inhibition assays for protein synthesis and proteasome were used to explore the mechanisms of ABT-263-enhanced Mcl-1 protein stability. Trypan blue exclusion assay and flow cytometry were used to examine cell death and apoptosis.
ABT-263 upregulated Mcl-1 mRNA and protein levels in HCC cells, which contributes to ABT-263 resistance. ABT-263 increased the mRNA level of Mcl-1 in HCC cells by enhancing the mRNA stability without influencing its transcription. Furthermore, ABT-263 increased the protein stability of Mcl-1 through promoting ERK- and JNK-induced phosphorylation of Mcl-1Thr163 and increasing the Akt-mediated inactivation of GSK-3β. Additionally, the inhibitors of ERK, JNK or Akt sensitized ABT-263-induced apoptosis in HCC cells.
ABT-263 increases Mcl-1 stability at both mRNA and protein levels in HCC cells. Inhibition of ERK, JNK or Akt activity sensitizes ABT-263-induced apoptosis. This study may provide novel insights into the Bcl-2-targeted cancer therapeutics.
Hepatocellular carcinoma (HCC) is one of the major causes of mortality in developing countries, such as in China, and its prevalence ranks the fifth of all tumors with rapid increasing morbidity . Currently, the efficacy of traditional chemotherapy for HCC is often unsatisfied . Therefore, it is of great priority to develop novel molecular targeted compounds. Recent studies have shown that the inhibitors of Bcl-2 exhibit promising antitumor activity .
Bcl-2 family consists of three categories of proteins, namely anti-apoptotic members, apoptosis executors and pro-apoptotic BH3-only proteins. The balance of these proteins contributes to survival and homeostasis of both normal and tumor cells . However, overexpression of anti-apoptotic members Bcl-2 and Bcl-xL always happens in tumors and indicates a poor prognosis [5–8]. Meanwhile, previous reports have also shown that the levels of Bcl-2/xL are closely related to the pathological grade and survival rate of HCC [9, 10]. These studies imply that Bcl-2/xL may serve as potential therapeutic targets for HCC.
Some of the Bcl-2 inhibitors (that have been) developed are a group of natural or synthesized compounds that target anti-apoptotic Bcl-2 family members especially Bcl-2 and Bcl-xL. ABT-263, also known as Navitoclax, is an orally available analog of ABT-737, which can bind to Bcl-2 and Bcl-xL, but not Mcl-1 . Several studies have shown that ABT-263 exerts optimistic anti-tumor effects, especially in haematological malignancies and non-small cell lung cancer . Furthermore, ABT-263 is now in phaseII clinical trials for several types of tumor with initial results [12, 13]. However, previous studies have shown that ABT-263 upregulates Mcl-1 protein, which ultimately contributes to drug resistance [14, 15].
Mcl-1 is an important anti-apoptotic protein that mainly distributes in mitochondria and cytoplasm. Mcl-1 exerts anti-apoptotic effects by interacting with pro-apoptotic proteins such as Bim, Noxa, Bak and Bax. Also, Mcl-1 may function by facilitating normal mitochondrial fusion, ATP production and respiration . Therefore, Mcl-1 protein level is elaborately regulated in both normal and tumor cells , among which phosphorylation modification is a quite significant way. Others reporting results and our previous data have shown that ABT-263 upregulates Mcl-1 in HCC cells, which is the crucial reason for ABT-263 resistance in cancer therapy. However, the associated mechanisms are not well known [14, 18]. In the present study, we for the first time demonstrated that ABT-263 upregulated Mcl-1 by enhancing the stability of both Mcl-1 mRNA and protein, which contributed to ABT-263 resistance in HCC cells. Moreover, inhibition of ERK, JNK or Akt activity sensitized ABT-263-induced apoptosis. This study may provide novel insights into the Bcl-2-targeted cancer therapeutics.
Upregulation of Mcl-1 is correlated with ABT-263 resistance in HCC cells
ABT-263 upregulates Mcl-1 at both mRNA and protein levels
ABT-263 increases the mRNA stability of Mcl-1
ABT-263 increases the protein stability of Mcl-1
Activation of ERK and JNK involves in ABT-263-induced stabilization of Mcl-1 protein
ABT-263 enhances ERK- and JNK-mediated Mcl-1Thr163 phosphorylation
To further investigate the concrete mechanisms of ERK- and JNK-mediated Mcl-1 stabilization, the phosphorylation status of Mcl-1Thr163 was analyzed. As shown in Figure 5E and F, inhibition of ERK or JNK significantly attenuated ABT-263-induced Mcl-1Thr163 phosphorylation and Mcl-1 accumulation, suggesting that the phosphorylation of Mcl-1Thr163 may contribute to ERK- and JNK-mediated Mcl-1 stabilization upon ABT-263 treatment in HCC cells.
Akt-mediated GSK-3β inactivation also involves in ABT-263-induced Mcl-1 stabilization
ABT-263, a newly-developed, oral-tolerant Bcl-2/xL inhibitor, has shown promising anti-tumor efficacy in non-small cell lung cancer and acute lymphoblastic leukemia as single agent both in vitro and in vivo. Meanwhile, ABT-263 can markedly sensitize several clinical drugs in cancer therapy [26, 27]. However, a recent study has demonstrated that HCC cells are relatively resistant to ABT-737 (analog of ABT-263) compared to leukemia and lung carcinomas . Furthermore, it has been indicated that ABT-737-induced Mcl-1 upregulation contributes to this resistance . Consistent with ABT-737, our results showed that both ABT-263 and another Bcl-2 inhibitor AT-101 upregulated Mcl-1 in HCC cells, which at last resulted in drug resistance. So it is important to clarify the associated mechanisms of ABT-263-induced Mcl-1 upregulation in HCC cells.
It is known that Mcl-1 is an important anti-apoptotic protein, which is now becoming a quite important target for cancer therapy . Characteristically, it has a short half-life and is elaborately regulated at different levels . We found that ABT-263 increased Mcl-1 mRNA level in HCC cells. It is also reported that Mcl-1 can be regulated by several transcription factors, including STAT3 , ATF4 , CREB  and HIF-1 . However, the luciferase assay results in this study demonstrated that ABT-263 did not increase the transcriptional activity of Mcl-1 promoter, indicating that these transcription factors may not play dominated roles in this process. Furthermore, we demonstrated that ABT-263 enhanced Mcl-1 mRNA stability in HCC cells. It is known that RNA stability is affected by various factors such as RNases and RNA binding proteins, but just only one RNA binding protein CUGBP2 has been reported to play a role in Mcl-1 mRNA stabilization . Therefore, it is unclear at present whether ABT-263-enhanced Mcl-1 mRNA stability is associated with CUGBP2, which is interesting and needs further studies.
Besides mRNA level, protein stability also plays important role in the upregulation of Mcl-1 protein. It is known that the phosphorylation of Mcl-1 is closely associated with Mcl-1 protein stabilization . Serine159 and Threonine163 are two important phosphorylation sites in Mcl-1 PEST region to determine the fate of Mcl-1 degradation. Mcl-1 can be phosphorylated by ERK at its Thr163 site, which prolongs the half life of this protein . ERK mediated-phosphorylation at Thr163 represents an important resistant mechanism in leukemia cells  and the inhibition of MEK/ERK sensitizes the anti-tumor effect of ABT-737 . Consistent with these reports, our study showed that ERK-mediated Thr163 phosphorylation of Mcl-1 contributed to ABT-263 resistance in HCC cells. JNK, another important member of MAPK family, can phosphorylate Mcl-1 at several sites, but the effect of JNK on Mcl-1 is varied . JNK-mediated Thr163 phosphorylation may lead to enhanced Mcl-1 degradation  or increased Mcl-1 stabilization . Our data demonstrated that ABT-263 increased JNK-mediated Mcl-1Thr163 phosphorylation, which enhanced Mcl-1 protein stability in HCC cells. Furthermore, both ERK and JNK inhibitors sensitized ABT-263-induced apoptosis and cell death by downregulating Mcl-1 in HCC cells, which may be novel ways to sensitize ABT-263 in HCC therapy.
GSK-3β plays an important role in glucose metabolism in mammalian cells. After being phosphorylated at Serine9, GSK-3β loses its activity. It is known that Mcl-1 can be phosphorylated by GSK-3β at Ser159 site, which decreases Mcl-1 stability . A recent study has shown that ABT-263 enhances the anti-tumor effect of PI3K inhibitor in GSK3-dependent manner in human myeloid leukemia cells, but the detailed mechanisms are still not clear . Our study demonstrated that ABT-263 promoted GSK-3β inactivation and Mcl-1 stability via Akt pathway, indicating that inhibition of Akt may be a good strategy to sensitize ABT-263 in HCC treatment.
It is well known that Bcl-2/xL are involved in regulating the homeostasis of apoptosis, autophagy and oxidative stress in the cells , which are associated with ERK, JNK and Akt pathways. ABT-263 is known as a specific inhibitor of Bcl-2/xL, so the mechanisms by which ABT-263 activates ERK, JNK and Akt may be complicated. Our previous data have shown that Bcl-2 inhibitor apogossypolone can induce reactive oxygen species (ROS) in HCC cells, which results in the activation of multiple vital signaling pathways including ERK, JNK and Akt pathways . In the present study, we demonstrated that ABT-263 could induce the phosphorylations of ERK, JNK and Akt, which were markedly attenuated by the widely used antioxidant N-acetyl-cysteine (Additional file 1: Figure S2), suggesting that ABT-263 may activates ERK, JNK and Akt via , at least partially, inducing ROS production.
In conclusion, our study demonstrates that ABT-263 upregulates Mcl-1 through increasing its mRNA and protein stability, which contributes to the resistance of ABT-263 in HCC cells. Inhibition of ERK-, JNK- or Akt-mediated Mcl-1 stability may confer Bcl-2 inhibitor better anti-tumor effect in HCC cells. Our results may provide more details to Bcl-2-targeted therapeutics and give insights into the future clinical trials of Bcl-2 inhibitors in HCC therapy.
Materials and methods
The cell culture reagents were purchased from Hyclone (Waltham, MA, USA). ABT-263, cycloheximide, SP600125, rapamycin, NVP-BEZ235 and N-acetyl-cysteine were purchased from Sigma-Aldrich (Louis, MO, USA). U0126, Act D, MG132, the antibody against α-tubulin, BCA protein assay kit and RIPA lysis buffer were purchased from Beyotime Biotechnology (Shanghai, China). AnnexinV-FITC/propidium iodide (PI) apoptosis detection kit was purchased from BD bioscience (BD, NJ, USA). Cell Counting Kit-8 (CCK-8) was from Dojindo (Shanghai, China). Trizol agent, M-MLV transcriptase and Lipofectamin 2000 were from Invitrogen (Carlsbad, CA, USA). SYBR qPCR master mix, PrimeSTAR HS DNA polymerase, restriction endonuclease Nhe Iand Hin dIII were from TAKARA (Shiga, Japan). pGL3-basic vector, pCMV-β-gal plasmid, luciferase assay and β-gal assay systems were from Promega (Madison, WI, USA). Antibodies of Mcl-1 and Bcl-2 were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Antibodies separately against Bcl-xL, PARP, phosphorylated ERK1/2 (p-ERK1/2, Thr202/Tyr204), total-ERK, p-JNK(Thr183/Tyr185), p-mTOR(Ser2448), p-Mcl-1(Thr163), p-Akt(Ser473), p-GSK-3β(Ser9) and total-GSK-3β were from Cell Signaling Technology (Boston, MA, USA). HRP-conjugated goat anti-rabbit and anti-mouse IgG were purchased from Zhongshan Company (Beijing, China). siRNAs to Bcl-2, Bcl-xL, USP9X and control siRNAs were from Dharmacon (Lafayette, CO, USA). pcDNA3-Bcl-2 and pcDNA3-Bcl-xL expression plasmids were kindly gifts from University of Michigan( pcDNA3.0 was used as negative control).
Human HCC cell lines PLC/PRF/5, HepG2, Huh7 and Hep3B were purchased from American Type Culture Collection (ATCC), and cultured in high-glucose DMEM (Dulbecco’s modified Eagle’s medium) with 10% FBS (fetal bovine serum), streptomycin (100 μg/mL) and penicillin(100 U/mL). These cell lines were originally tested by ATCC and passaged less than 6 months in the lab.
Quantitative polymerase chain reaction (qPCR)
After treatment, the cells were lysed and total RNA was extracted with Trizol agent as described , and first-strand cDNA was synthesized using M-MLV transcriptase. qPCR was performed to detect the level of Mcl-1 mRNA using SYBR qPCR master mix in a 25 μl volume according to the manufacturer’s instruction. The sequences of different primers were as follows: Mcl-1: forward primer 5′-AAAGCCTGTCTGCCAAAT-3′ and reverse primer 5′-CCTATAAACCCACCACTC-3′; USP9X: forward primer 5′-CCTGCTGGTGCACCTCTGGC-3′ and reverse primer 5′-AGGCCGGTGTCCCATGCAA-3′; β-actin: forward primer 5′-ATCGTGCGTGACATTAAGGAGAAG-3′ and reverse primer 5′-AGGAAGGAAGGCTGGAAGAGTG-3′.
After treatment, the cells were harvested and whole-cell lysates were prepared. The protein concentrations were measured by BCA protein assay kit. Subsequently, Western blot analysis was performed as described .
Transfection of siRNA and Bcl-2/xL expression plasmid
The HCC cells were separately transfected with siRNAs to Bcl-2 (or Bcl-xL or USP9X) and control siRNA using Lipofectamine 2000 according to the manufacturer’s instruction. Similarly, the expression plasmid pcDNA3-Bcl-2 or pcDNA3-Bcl-xL was transfected into the corresponding HCC cells, taking pcDNA3.0 as negative control.
Cell viability assay
Cell viability assay was performed by using Cell Counting Kit-8 (CCK-8). Briefly, cells were seeded in triplicate in 96-well plates and given different treatments for indicated time, then the OD value at 450 nm was detected according to the manufacturer’s instruction.
Human Mcl-1 promoter regions −3009 to +251(M1) and −607 to +251(M2) were amplified by PCR using PrimeSTAR HS DNA polymerase taking genomic DNA of HepG2 cells as template. The two PCR fragments were separately inserted into pGL3-basic vector after digestion with restriction endonucleases Nhe I and Hin dIII, and the resulting plasmids were named as pLucM1 and pLucM2, respectively.
Luciferase reporter assay
PLC and Huh7 cells were seeded in 48-well plates and were co-transfected with pLucM1 or pLucM2 and monitor plasmid pCMV-β-gal using Lipofectamin 2000 according to the manufacturer’s protocol. After 36 h, the cells were lysed, and luciferase activity and β-gal activity were separately detected using Promega luciferase and β-gal assay systems according to the manufacturer’s protocols. The luciferase activity was normalized against β-gal activity. The transfection experiments were performed at least three times in triplicate. Data were represented as fold induction by normalizing the luciferase activity of the tested sample to that of the corresponding control sample.
Trypan blue exclusion assay
The trypan blue exclusion assay was performed as described . The total death rate (%) = numbers of dead cells/(numbers of living cells + numbers of dead cells) × 100.
After treatment, the HCC cells were harvested and incubated with annexin V-FITC and PI according to the manufacturer’s instructions. Then the apoptosis were analyzed by a flow cytometer.
The data were expressed as Mean ± SD. Two-way t-test and ANOVA were used to analyze the variance. P < 0.05 was defined as statistically significant.
This study was supported in part by Chongqing Natural Science Foundation (cstc2011BB5030 and 2013jjB10015), the National Natural Science Foundation of China (31201068, 81273226 and 81228005) and the Scientific Funds of Third Military Medical University (2011XHG02 and 2012XZH01).
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