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Am J Physiol Renal Physiol 294: F577-F581, 2008. First published December 19, 2007; doi:10.1152/ajprenal.00487.2007
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Restoration of CREB function ameliorates cisplatin cytotoxicity in renal tubular cells

Istvan Arany, Johann Herbert, Zsolt Herbert, and Robert L. Safirstein

Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas

Submitted 19 October 2007 ; accepted in final form 13 December 2007


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
We have shown that mouse proximal tubule cells (TKPTS) survive H2O2 stress by activating the cAMP-responsive element binding protein (CREB)-mediated transcription via the canonical EGFR-Ras/ERK pathway. By contrast, cisplatin activates EGFR/Ras/ERK signaling in TKPTS cells yet promotes cell death rather than survival. We now demonstrate that the cisplatin-induced activated EGFR/Ras/ERK signaling cascade fails to activate CREB-mediated transcription even in the presence of phosphorylated CREB. CREB-mediated transcription as well as survival was restored by the histone deacetylase (HDAC) inhibitor trichostatine A (TSA), an effective chemotherapeutic agent. Similar to severe oxidant stress, TSA-mediated survival could be abrogated by inhibition of CREB-mediated transcription. These studies confirm the importance of CREB-mediated transcription in the survival of renal cells subjected to either oxidant- or cisplatin-induced stress. The use of cisplatin and TSA in combined chemotherapy protocols may be an effective strategy to enhance cancer cell death and limit nephrotoxicity.

renal; survival

THE CAMP-RESPONSIVE ELEMENT binding protein (CREB) is important in the survival of a variety of cell types under different stress conditions (5, 8, 13, 15). Earlier, we found that during oxidant injury activation of the extracellular signal-regulated kinase (ERK) and consequent induction of CREB-mediated transcription is essential for survival of mouse proximal tubule cells (3, 4). CREB activation is mediated, at least in part, by the activated ERK (5, 20). By contrast, ERK contributes to the death of proximal tubule cells in cisplatin-induced nephrotoxicity (2). We interrogated possible sites of divergence between cisplatin- and oxidant-induced ERK activation and found that unlike oxidant stress, cisplatin-induced ERK-dependent phosphorylation of CREB was not followed by its transcriptional activation. Our studies now show that histone deacetylase (HDAC) inhibitors, which are known to reverse transcriptional repression and gene silencing induced by HDACs (18), is capable of restoring CREB transcriptional activation (6, 16). Importantly this report further establishes the role of CREB transcription in the survival of renal cells under stress.


   MATERIALS AND METHODS
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 MATERIALS AND METHODS
RESULTS
 DISCUSSION
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Cells and treatment. The immortalized mouse proximal tubule cell line (TKPTS) was a gift from Dr. E. Bello-Reuss (9) and was maintained as described previously (3, 7). Subconfluent cultures were treated with 25 µM cisplatin for the time points described in RESULTS.

Analysis of cell viability. Viable cell count was determined by trypan blue (Sigma, St. Louis, MO) exclusion in a hemocytometer. Cell morphology was determined by light microscopy using a Nikon Eclipse TE200 microscope equipped with Hoffman Modulation Contrast Optics. In addition, cell cycle analysis was performed by propidium iodide (PI) staining. TKPTS cells were collected after trypsinization and fixed in 70% ethanol overnight. After RNAse treatment, cells were incubated with 5 µg/ml PI and analyzed with a Becton-Dickinson FACSCalibur analyzer. The cell cycle profile was analyzed using CellQuest software. Cells residing in the subGo/G1 phase were considered to be apoptotic.

Adenoviral infection of TKPTS cells. The M1-CREB mutant adenovirus (19) was a gift from Dr. A. J. Zeleznik. The adeno-green fluorescent (adGFP) adenovirus was provided by Dr. H. Kaneto (10). TKPTS cells grown in six-well-plates were infected with 25 multiplicity of infection (MOI) adenovirus at 37°C overnight and then treated with different agents, as described in RESULTS. For molecular analysis, total cell lysates from these cells were prepared as described below. The efficiency of infection was determined by a control adenovirus (adGFP) as described earlier (10). The efficiency of infection was ~80% (data not shown).

Protein isolation and Western blotting. Monolayers of TKPTS cells were lysed in RIPA buffer that contained 100 µg/ml phenylmethylsulfonyl fluoride (Sigma, St. Louis, MO), 100 mM sodium orthovanadate (Sigma), and 50 µl/ml of proteinase inhibitor cocktail (Sigma) as described earlier (3). Protein content was determined by using a Bio-Rad Protein Determination assay (Bio-Rad Hercules, CA) as described earlier (3). One hundred micrograms of proteins from cell lysates were separated by SDS-PAGE and transferred to a polyvinylidene difluoride membrane (Bio-Rad). The filters were hybridized with the appropriate primary antibodies followed by a horseradish peroxidase-conjugated secondary antibody. The bands were visualized by an ECL method (Amersham) and quantified by densitometry (UnScan-It Gel v6.1, Silk Scientific, Orem, UT). Antibodies against phospho-CREB (Ser133) and caspase-3 were purchased from Cell Signaling Technology (Beverly, MA). Anti-rabbit horseradish peroxidase-conjugated secondary antibody was purchased from Cell Signaling Technology.

Reporter activation assay. The pCRE-Luc plasmid, which contains four direct repeats of consensus CRE binding sites, was purchased from Stratagene (La Jolla, CA). The pCRE-Luc plasmid was transiently transfected into TKPTS cells together with a β-galactosidase plasmid (Invitrogen) using a GenePorter2 reagent (GenLantis, San Diego, CA ) as described earlier (1).

Luciferase activity was determined by using a Luciferase Assay kit as suggested by the manufacturer (Promega, Madison, WI) under control conditions as well as 1, 6, and 12 h after incubation with cisplatin. This last time point was chosen because cells show no obvious damage at this time. The relative luciferase activity was measured and was normalized to the amount of activity detected for a cotransfected β-galactosidase plasmid.

Statistical analysis. Continuous variables are expressed as means ± SD. Means of multiple treatment groups were compared with controls by using of ANOVA with a post hoc test. A P value of ≤0.05 was considered statistically significant. All analyses were performed using a SigmaStat 3.5 software package.


   RESULTS
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DISCUSSION
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Cisplatin increases serine 133 phosphorylation of CREB but not CREB-mediated transcription. CREB is a downstream target of ERK (5, 20), and we first determined whether serine 133-phosphorylated CREB (pCREB) occurred after cisplatin treatment. Western blots of cisplatin-treated TKPTS cells show prominent CREB phosphorylation at the indicated time points (Fig. 1, A and B). We next examined whether this increased phosphorylation would be accompanied by an elevated CREB-mediated transcription. Surprisingly, pCRE-Luc activity not only failed to increase but actually decreased 6 or 12 h after treatment with cisplatin (Fig. 1C). The most prominent changes were observed at 12 h posttreatment; thus we used this time point in further experiments. There is no indication of cell death 12 h after treatment (data not shown).


Figure 1
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  		Fig. 1. Effects of cisplatin treatment on the cAMP-responsive element binding protein (CREB) phosphorylation and pCRE-Luc activity. A: TKPTS cells were treated with 25 µM cisplatin for the time points indicated. Serine 133-phosphorylated CREB together with the total CREB were determined by Western blotting. B: densitometric analysis of blots shown in A. Values are expressed as ratios of phospho-CREB and total CREB (means ± SD, n = 3). *P < 0.05, multiple comparison vs. control group by ANOVA with post hoc test. C: TKPTS cells were transiently transfected with a pCRE-Luc and a β-galactosidase plasmid for 24 h. Cells then were treated with 25 µM cisplatin for the time points indicated, and luciferase activity was determined together with the β-galactosidase. Luciferase values are normalized to β-galactosidase and expressed as percentage of control value (means ± SD; n = 3). *P < 0.05, multiple comparison vs. control group by ANOVA with post hoc test.

 
These results suggest that serine 133 phosphorylation of CREB itself is not sufficient for induction of CREB transcription and a consequent survival.

TSA increases CREB phosphorylation, restores CREB-mediated transcription, and ameliorates cell death during cisplatin-induced cytotoxicity. Since TSA has been shown to increase CREB activity (6), we next determined whether TSA affects CREB phosphorylation and its transcriptional activity. Accordingly, TKPTS cells were pretreated with 50 nM TSA for 4 h and then treated with cisplatin for 4 h. CREB phosphorylation was determined by Western blotting. TSA alone increased CREB phosphorylation, which was even further increased in the presence of cisplatin, probably in an additive fashion (Fig. 2, A and B). Importantly, in the pCRE-Luc assay both TSA and the combination of TSA plus cisplatin significantly increased luciferase activity at the indicated time points (Fig. 2C). These results suggest that TSA treatment restores CREB-mediated transcription.


Figure 2
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  		Fig. 2. Effects of trichostatine A (TSA) on cisplatin-induced CREB phosphorylation and CREB-mediated transcription. A: TKPTS cells were pretreated with 50 nM TSA 4 h before treatment with 25 µM cisplatin for 4 h. Cell lysates were prepared, and serine 133-phosphorylated CREB together with the total CREB were determined by Western blotting. B: densitometric analysis of blots shown in A. Values are expressed as ratios of phospho-CREB and total CREB (means ± SD, n = 3). *P < 0.05, multiple comparison vs. control group by ANOVA with post hoc test. C: TKPTS cells were transiently transfected with a pCRE-Luc and a β-galactosidase plasmid for 24 h. Cells then were treated with 25 µM cisplatin for 6 and 12 h, and luciferase activity was determined together with β-galactosidase. Luciferase values are normalized to β-galactosidase and expressed as a percentage of control value (means ± SD, n = 3). *P < 0.05, multiple comparison vs. control group by ANOVA with post hoc test.

 
Next, we determined whether TSA pretreatment affects cisplatin-induced cell death. TKPTS cells were pretreated with 50 nM TSA 4 h before treatment with 25 µM cisplatin for 24 h, and cell counts were determined. As seen in Fig. 3, TSA pretreatment significantly increased cell survival after treatment with cisplatin (from 41 to 79%). TSA alone inhibited cell growth (~30% compared with the untreated cells); thus, for a better comparison, we used untreated cells as controls for cisplatin treatment and TSA-treated cells for TSA plus cisplatin. Surprisingly, TSA treatment did not affect cell viability or cell cycle progression (Fig. 4A). FACS analysis also confirmed the effect of TSA on cisplatin-induced cell death: TSA pretreatment significantly decreased the number of dead (subG0/G1) cells induced by cisplatin from 56.3 to 29.5% without affecting cell cycle distribution (Fig. 4A). Also, TSA pretreatment significantly inhibited cisplatin-mediated caspase-3 activation (Fig. 4B), further demonstrating the prosurvival role of TSA.


Figure 3
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  		Fig. 3. Effects of TSA on survival of TKPTS cells during cisplatin (CP) nephrotoxicity. TKPTS cells were pretreated with 50 nM TSA 4 h before treatment with 25 µM cisplatin for 24 h. Cells were trypsinized, and Trypan blue-negative (survival) cells were counted. Results are given as percentage of control (untreated or TSA-treated, respectively; means ± SD, n = 3). *P < 0.05, multiple comparison vs. control group by ANOVA with post hoc test.

 

Figure 4
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  		Fig. 4. Effects of TSA treatment on cell cycle progression and caspase-3 activity. TKPTS cells were pretreated with 50 nM TSA 4 h before treatment with 25 µM cisplatin for 24 h. A: cell cycle progression was determined by FACS analysis. The number of dead (subG1/G0) cells are given as a percentage of total cell number. B: cell lysates were prepared after 24-h treatment and subjected to SDS-PAGE. The amount of activated (cleaved) caspase-3 was determined by Western blotting. Densitometric data are shown. *P < 0.05, multiple comparison vs. control group by ANOVA with post hoc test.

 
Inhibition of CREB attenuates TSA-induced CREB-transcription and survival during cisplatin-induced nephrotoxicity. To demonstrate the role of TSA-induced and CREB-mediated transcriptional events in survival during cisplatin-induced cytotoxicity, TKPTS cells were infected with 25 MOI of a mutant (M1-CREB) adenovirus (19) for 18 h. The M1-CREB mutant competes with endogenous CREB for binding to CREB-responsive elements. As a control, TKPTS cells were infected with the adGFP adenovirus. The M1-CREB mutant attenuated TSA- and TSA+CP-induced pCRE-Luc activity while adGFP did not (Fig. 5).


Figure 5
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  		Fig. 5. Effects of CREB inhibition on TSA-induced pCRE-Luc activity. A: TKPTS cells were transiently transfected with a pCRE-Luc and a β-galactosidase plasmid for 24 h. Cells then were pretreated with 50 nM TSA for 4 h before treatment with 25 µM cisplatin for 12 h in the presence or absence of 25 multiplicity of infection (MOI) M1-CREB or adGFP adenovirus. Luciferase activity was determined together with the β-galactosidase. Luciferase values are normalized to β-galactosidase and expressed as percentage of control (means ± SD, n = 3). *P < 0.05, multiple comparison vs. control group by ANOVA with post hoc test.

 
Also, M1-CREB but not adGFP attenuated TSA-induced survival after treatment with cisplatin (Fig. 6). M1-CREB and adGFP alone did not affect cell survival significantly, as described elsewhere (3, 4). These data demonstrate a direct link between CREB transcriptional activation and survival similar to that observed after oxidant injury (4).


Figure 6
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  		Fig. 6. Effects of CREB inhibition on TSA-induced survival in the presence of cisplatin. TKPTS cells were pretreated with 50 nM TSA 4 h before treatment with 25 µM cisplatin for 24 h in the presence or absence of 25 MOI M1-CREB or adGFP adenovirus. Cells were trypsinized and counted with Trypan blue. Results are given as percentage of control (untreated or TSA-treated) values (means ± SD, n = 3). *P < 0.05, multiple comparison vs. control group by ANOVA with post hoc test.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Activated CREB is crucial for survival of neural, muscle, or other cell types during a variety of stress conditions including hypoxia and DNA damage (5, 8, 13, 15). We showed that TKPTS cells survive oxidant stress by activating CREB-mediated transcription via the canonical EGFR-Ras/ERK pathway (4). Here, we found that even though cisplatin increases phosphorylation of CREB (Fig. 1, A and B) it does not activate CREB-mediated transcription (Fig. 1C). In this regard, cisplatin would seem to be similar to LPS-induced stress in hepatocytes, where LPS treatment increases CREB phosphorylation but CREB-mediated reporter activity actually falls (21). In those studies, it is thought that the inhibition is served by cytokine activation of c-Jun. A similar situation may exist in cisplatin nephrotoxicity, as c-Jun is prominently expressed during cisplatin exposure (17).

Aware of the effect of cisplatin on reducing histone acetylation in cancer cells (14) and the effect of HDAC inhibitors such as TSA to enhance CREB-driven transcription (6, 16), we sought to determine the effect of TSA on CREB-mediated transcription and whether such a reversal would enhance survival in cisplatin-treated cells.

Pretreatment of TKPTS cells with TSA restored pCRE-luc activity and increased the survival of cells exposed to cisplatin (Figs. 2–4). Inhibition of CREB function via a mutant CREB adenovirus (19) significantly diminished both TSA-induced CREB-mediated transcription (Fig. 5) and survival (Fig. 6) during cisplatin nephrotoxicity. These experiments proved that TSA-induced survival is mediated through CREB-mediated transcriptional events. Presumably, the restoration of CREB transcription is mediated either by a gain of an activating cofactor or by the loss of a transcriptional regulator at target CRE sites (14). The inhibition of caspase-3 activation by restoring CREB transcription places this pathway upstream of caspase-3 activation (Fig. 4B) in the proapoptotic pathway initiated by cisplatin.

Another important implication of our findings is the fact that HDAC inhibitors increase antitumor effects of DNA-damaging agents such as cisplatin (12). As we now show that TSA abrogates cisplatin-induced cytotoxicity in renal cells (Figs. 4–6), this difference between renal cells and cancer cells may be exploited clinically to enhance the therapeutic index of cisplatin when both drugs are combined.

In summary, the HDAC inhibitor TSA increased CREB-dependent transcription and consequent survival of renal tubular cells probably by reversing CREB-mediated gene repression during cisplatin-induced cytoxicity in renal tubular cells. Identifying the mechanism by which TSA activates CREB-mediated transcription may provide additional potential targets to ameliorate the nephrotoxicity of cisplatin and other cellular stressors that damage kidney cells.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
Financial support was provided by National Institute of Diabetes and Digestive and Kidney Diseases Grant PO1-DK-58324-01A1 (to R. L. Safirstein) and an American Heart Heartland Affiliate Grant-in-Aid 0655716Z (to I. Arany). This work was supported in part with resources and the use of facilities at the Central Arkansas Veteran Healthcare System, Little Rock, AR.


   ACKNOWLEDGMENTS
 
We thank Dr. A. J. Zeleznik for the mutant M1-CREB adenovirus and Dr. H. Kaneto for adGFP, as well as Dr. J. K. Megyesi for valuable suggestions.


   FOOTNOTES
 

Address for reprint requests and other correspondence: I. Arany, Dept. of Pediatrics, Div. of Pediatric Nephrology, Univ. of Mississippi Medical Center, 2500 N. State St, Jackson, MS 39216 (e-mail: iarany{at}ped.umsmed.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address of I. Arany: Dept. of Pediatrics, Div. of Pediatric Nephrology, Univ. of Mississippi Medical Center, Jackson, MS.

Present address of J. Herbert and Z. Herbert: Dept. of Internal Medicine, Univ. of Kentucky, Lexington, KY.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
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  1. Arany I, Grattendick KG, Tyring SK. Interleukin-10 induces transcription of the early promoter of human papillomavirus type 16 (HPV16) through the 5'-segment of the upstream regulatory region (URR). Antiviral Res 55: 331–339, 2002.[CrossRef][Medline]
  2. Arany I, Megyesi JK, Kaneto H, Price PM, Safirstein RL. Cisplatin-induced cell death is EGFR/src/ERK signaling dependent in mouse proximal tubule cells. Am J Physiol Renal Physiol 287: F543–F549, 2004.[Abstract/Free Full Text]
  3. Arany I, Megyesi JK, Kaneto H, Tanaka S, Safirstein RL. Activation of ERK or inhibition of JNK ameliorates H2O2 cytotoxicity in mouse renal proximal tubule cells. Kidney Int 65: 1231–1239, 2004.[CrossRef][Web of Science][Medline]
  4. Arany I, Megyesi JK, Reusch JE, Safirstein RL. CREB mediates ERK-induced survival of mouse renal tubular cells after oxidant stress. Kidney Int 68: 1573–1582, 2005.[CrossRef][Web of Science][Medline]
  5. Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286: 1358–1362, 1999.[Abstract/Free Full Text]
  6. Canettieri G, Morantte I, Guzman E, Asahara H, Herzig S, Anderson SD, Yates JR 3rd, Montminy M. Attenuation of a phosphorylation-dependent activator by an HDAC-PP1 complex. Nat Struct Biol 10: 175–181, 2003.[CrossRef][Web of Science][Medline]
  7. di Mari JF, Davis R, Safirstein RL. MAPK activation determines renal epithelial cell survival during oxidative injury. Am J Physiol Renal Physiol 277: F195–F203, 1999.[Abstract/Free Full Text]
  8. Du K, Montminy M. CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem 273: 32377–32379, 1998.[Abstract/Free Full Text]
  9. Ernest S, Bello-Reuss E. Expression and function of P-glycoprotein in a mouse kidney cell line. Am J Physiol Cell Physiol 269: C323–C333, 1995.[Abstract/Free Full Text]
  10. Kaneto H, Xu G, Fujii N, Kim S, Bonner-Weir S, Weir GC. Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression. J Biol Chem 277: 30010–30018, 2002.[Abstract/Free Full Text]
  11. Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, Carrier F. Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63: 7291–7300, 2003.[Abstract/Free Full Text]
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  13. Mayr B, Montminy M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol 2: 599–609, 2001.[CrossRef][Web of Science][Medline]
  14. Mehrhof FB, Muller FU, Bergmann MW, Li P, Wang Y, Schmitz W, Dietz R, von Harsdorf R. In cardiomyocyte hypoxia, insulin-like growth factor-I-induced antiapoptotic signaling requires phosphatidylinositol-3-OH-kinase-dependent and mitogen-activated protein kinase-dependent activation of the transcription factor cAMP response element-binding protein. Circulation 104: 2088–2094, 2001.[Abstract/Free Full Text]
  15. Michael LF, Asahara H, Shulman AI, Kraus WL, Montminy M. The phosphorylation status of a cyclic AMP-responsive activator is modulated via a chromatin-dependent mechanism. Mol Cell Biol 20: 1596–1603, 2000.[Abstract/Free Full Text]
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