IN PERSPECTIVE

Targeting Bcl-XL for Prevention and Therapyof Skin Cancer

Jack Zhang and G. Tim Bowden*

Arizona Cancer Center, University of Arizona, 1515 N. Campbell, Tucson, Arizona 85724

Apoptosis plays an important role in skin carcinogenesis. Bcl-XL, an antiapoptotic Bcl-2 family member, is a keyregulator in the process. Aberrant expression of Bcl-XL allows cells carrying mutations to survive and propagate.

Overexpression of Bcl-XL is correlated with tumor malignancy and invasion. Importantly, deregulation of Bcl-XL confersdrug resistance to chemotherapy. Therefore, targeting Bcl-XL in combination with conventional chemotherapy is apromising way to pursue cancer chemotherapy. Several compounds targeting Bcl-XL expression or function have

shown their potential in chemoprevention and of chemotherapy of cancer. � 2007 Wiley-Liss, Inc.

Key words: skin cancer; apoptosis; Bcl-XL

INTRODUCTION

Human skin is constantly exposed to variousstressful and damaging conditions and is thereforeprone to skin cancer. Not surprisingly, more thanonemillionnew cases of skin cancer are diagnosed inthe United States every year, accounting for 40% ofall cancer cases. Among them, malignant melano-mas consist of 4%,while 96%arenonmelanoma skincancers (NMSCs). NMSCs can be further classifiedinto basal-cell carcinomas (BCCs) and squamous-cellcarcinomas (SCCs). Both are derived from the basallayer of the epidermis of the skin [1].Ultraviolet (UV) irradiation is the primary etiolo-

gical factor for skin carcinogenesis. The UV irradia-tion can be categorized into UVA (320–400 nm),UVB (280–320 nm), and UVC (200–280 nm), basedon their wavelength. However, UVC is absorbed bythe ozone layer before reaching the earth. Therefore,only UVA (90–99% of sunlight) and UVB (1–10% ofsunlight) are considered biologically relevant to skincarcinogenesis [1].UV irradiationcausesDNAphoto-damage and production of reactive oxygen species(ROS), which can also damage DNA. The primaryDNA damage induced by UV includes cyclobutanepyrimidine dimers andpyrimidine-pyrimidone dim-mers [2]. These DNA lesions are recognized andrepaired by nucleotide-excision repair (NER)mechanism. The importance of NER can be illu-strated by a genetic disorder, xeroderma pigmento-sum (XP). XP is caused by defects in one of sevengenes in NER pathway (XPA-XPG). The XP patientsare sensitive to sun exposure, and develop skincancer at a very early age. The risk of skin cancer inthese patients is 1000 times higher than the generalpopulation [3].On the other hand, it is known that the efficiency

of DNA repair is not sufficient to eliminate allgenerated lesions in proliferating basal keratino-

cytes. To avoid the accumulation of mutations, theskin has developed another defense mechanism:apoptosis, a primary mechanism to eliminate cellsthat are potentially harboringmutations. Because ofapoptosis, an adult flakes off approximately 1.5 g ofkeratinocytes from the epidermis a day. The regen-eration of epidermis is precisely balanced by con-tinuous production of new cells from stem cells inthe basal layer of the epidermis. It was estimated thata new layer of keratinocytes will be generated every9–11 d in the mouse.Therefore, it has been proposed that deregulation

of apoptosis is a critical hallmarkof carcinogenesis byallowing clonal expansion of cells carrying certainmutations such as those favoring cell division, self-sustained growth, or metastasis [4]. For example,mutations in the tumor suppressor p53 weredetected in more than 90% of SCC and 56% of BCCcells. In this review, we discuss the role of Bcl-XL, anantiapoptotic Bcl-2 family member in skin carcino-genesis as a potential chemoprevention and che-motherapy target.

Antiapoptotic Role of Bcl-XL

There are two apoptotic pathways in mammaliancells, intrinsic and extrinsic. The central regulators ofboth pathways are the Bcl-2 (B cell lymphoma)family members. The identification of Bcl-2 led to

MOLECULAR CARCINOGENESIS 46:665–670 (2007)

� 2007 WILEY-LISS, INC.

Abbreviations: SCC, squamous-cell carcinoma; UV, ultraviolet;NER, nucleotide-excision repair; XP, xeroderma pigmentosum; DISC,death-inducing signaling complex; HDAC, histone deacetylase; NaB,sodium butyrate.

*Correspondence to: Arizona Cancer Center, University ofArizona, 1515 N. Campbell, Tucson, AZ 85724.

Received 31 January 2007; Revised 5 March 2007; Accepted 6March 2007

DOI 10.1002/mc.20330

the finding of other family members based on theconserved BH (Bcl-2 homology) domains. Differentfamily members possess either antiapoptotic orproapoptotic functions [5].In the intrinsic pathway, cell death signals, such as

DNA damage, promote two proapoptotic Bcl-2family members, Bax and Bak to migrate to mito-chondrial membranes. Subsequently, Bax and Bakoligomerize on the outer mitochondrial membraneand thus change the permeability of the mitochon-dria, leading to the release of small moleculesincluding cytochrome c. Subsequently, in the pre-sence of ATP, cytochrome c binds to apoptosis-activating factor 1 (Apaf-1), andprocaspase-9 to formthe apoptosome. This complex in turn activatescaspase-9 and the downstream cascade includingactivation of caspases-8 and caspase-3, committingto cell death [5] (Figure 1).The extrinsic apoptotic pathway is triggered by Fas

ligand (FasL) that binds to Fas (also known as CD95orAPO-1), a transmembrane receptor. This interac-tion enables the cytoplasmic death domain (DD) ofFas to recruit Fas-associated death domain (FADD)and procaspase-8, forming the death-inducing sig-naling complex (DISC). This complex, in turn, leadsto the activation of caspase-3 and cell death.Alternatively, DISC can cleave and activate Bid,which activates the intrinsic pathway by promotingBax andBakoligomerizationonto themitochondrialmembrane [5] (Figure 1).Bcl-XL, predominantly localized on themitochon-

drial outer membrane, plays a critical role maintain-ing cellular homeostasis because it has been shownto inhibit both the intrinsic and extrinsic pathways.Bcl-XLhas fourBH(Bcl-2homology) domainsBH1-4,likeother antiapoptoticmolecules in this family. TheBH1-3 domains form an elongated hydrophobicgroove, serving as the docking site for the BH3domains of proapoptotic binding partners [6]. It hasbeen postulated that Bcl-XL prevents Bax and Bakfrom forming chain structures. In this model, uponmigrating to the mitochondrial outer membrane,Bax and Bak form chain-like polymers and thusdisrupt the mitochondrial membrane. Bcl-XL stopsthe further growth of these chains by latching ontotheir ends [7]. By this means, Bcl-XL inhibits theintrinsic pathway.Bcl-XL also binds to Bid, preventing its interaction

with Bax/Bak and their translocation to the mito-chondrialmembrane.Moreover, Bcl-XLwas found toinhibit caspase-8 cleavage and disrupt DISC forma-tion [8]. These authors also found that Bcl-XL mayupregulate FLIP, an endogenous caspase-8 inhibitor.Thus, Bcl-XL is able to repress the extrinsic pathway(Figure 1).Numerous studies support the antiapoptotic role

of Bcl-XL in skin. In vitro studies showed that Bcl-XL

protects melanocytes and HaCaT (immortalizedhuman keratinocyte) cells from UV induced apop-

tosis. For example, Jost et al. showed thatHaCaT cellsundergo apoptosis 24 h after being treated with 150or 300 mJ/cm2 UVB. In contrast, overexpression ofBcl-XL enhanced cell survival dramatically. More-over, theseBcl-XLoverexpressing cells are resistant tocell death induced by forced suspension (anoikis)and inhibition of epidermal growth factor receptor(EGFR) by AG1478 [9]. Importantly, our laboratoryhas shown that UVA irradiation can increase theexpression of Bcl-XL markedly, providing a causalrelationship with skin carcinogenesis. Ectopicexpression of Bcl-XL protects HaCaT cells fromapoptosis induced by the inhibition of p38 afterUVA irradiation [10]. In vivo, overexpression of Bcl-XL is able to inhibit the apoptotic response tochemical carcinogens DMBA/TPA. Pena et al. [11]found that the epidermis of Bcl-XL transgenic micetreated with DMBA/TPA had significantly fewerapoptotic cells than the wild-type control mice,emphasizing the importance of Bcl-XL in skincarcinogenesis.Conversely, inhibition of Bcl-XL leads to apopto-

sis. For example, in human keratinocytes, blocking

Figure 1. Apoptosis can be triggered by two independent butcross-talking pathways, intrinsic, and extrinsic. In the intrinsicpathway, death signals such as extensive DNA damage cause themigration of two proapoptotic molecules, Bax and Bak to themitochondria, where they change the permeability of the mitochon-dria membrane, resulting in a leakage of cytochrome c. Byinteracting with Apaf-1 and procaspase-9, cytochrome c promotesthe assembly of the apoptosome that activates the caspase casade,caspase-9, caspase-8, and caspase-3, leading to cell death. In theextrinsic pathway, Fas ligand (FasL) binds to the transmembranereceptor Fas, causing a conformational change in the Fas cytoplasmicterminus. As a result, the death domain (DD) recruits procaspase-8and Fas-associated death domain (FADD) to form death-inducingsignaling complex (DISC). This complex activates caspase-3 and leadsto cell death directly. Alternatively, DISC can cleave Bid. Thetruncated Bid (tBid) is able to promote the migration of Bax andBak to the mitochondria, thus activating the intrinsic pathway. It hasbeen shown that Bcl-XL can prevent both pathways by blockingboth Bax/Bak function in the mitochondria and tBid interaction withBax/Bak.

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EGFR by its specific antibody or AG1478 reduced Bcl-XL, but not Bcl-2, resulting in apoptosis [9]. A morespecific study showed that inhibition of Bcl-XL by itsantisense oligo (ISIS 16009) dramatically increasedthe percentage of apoptotic human neonatal kerati-nocytes (hKn) from 2.4% of the control (no oligo) to37.9% [12].

Expression of Bcl-XL Correlates With Skin TumorIncidence and Malignancy

Because resistance to apoptosis is an importantmechanism of carcinogenesis, numerous clinicaland animal studies have explored the role of Bcl-XL

in skin carcinogenesis. It was found that in twomelanoma cell lines, YUSAC2 and YUSIT1, there isremarkably higher Bcl-XL expression than in normalmelanocytes. Several independent clinical studiescorroborated this finding [13]. A roughly 20 or 40%increase of Bcl-XL mRNA levels were detected inprimary or metastasized melanoma tissues, respec-tively. Importantly, metastasizedmelanoma expresseshigher Bcl-XL than their matched primary tumors.The studies also showed that Bcl-XL renders primaryand metastasized melanoma cells resistant to UVB-irradiation, as the protein level of Bcl-XL, but not Bcl-2 is inversely correlated with apoptotic rates in thesecells [14]. Conversely, treatment of melanoma cellswith 600 nM of antisense Bcl-XL oligo that inhibitsBcl-XL expression dramatically increased melanomacell death up to 75%. Consequently, these studieshave raised the possibility that levels of Bcl-XL maybe used for the prognosis of melanomas. Actually,Bcl-XL expression is a good prognostic marker inesophagus SCC, with a positive correlationwith SCCinvasion and metastasis [15].A critical study from Pena et al. [11] clearly

established the causal effect of Bcl-XL and skincarcinogenesis by constructing transgenic mice thatexpress Bcl-XL under control of the keratin K14promoter. In their two-stage chemical carcinogen-esis protocol, both the transgenic and the wild-typemice were treated with DMBA and TPA. The devel-opment of papillomas and carcinomas was mea-sured. Despite the fact that papillomas developed atthe same time period (�5 wk after initiation) in bothgroups, the number of papillomas in the transgenicmice was approximately twofold higher than that ofthe wild-type. Significantly, more than half of thetransgenicmice developed squamous cell carcinomawithin 7 mo of DMBA treatment, whereas none ofthe wild-type mice had SCC at the same time.Moreover, invasive carcinomas in the transgenicmice were significantly more advanced than carci-nomas in the wild-type mice. The malignant lesionson the Bcl-XL transgenic mice invaded into thedermis and underlying muscular layers, while thewild-type mice developed only benign papillomas.Finally, multiple lung metastases were found in oneof the K14- Bcl-XL transgenic mice, whereas no

metastatic tumors were observed in any of the wild-type mice [11].

Bcl-XL Confers Drug Resistance

Several lines of evidence indicate that overexpres-sion of Bcl-XL leads to drug resistance in cancer. First,there is a strong correlation between the elevatedexpression of Bcl-XL and cancers, including skin.Head and neck squamous cell carcinoma (HNSCC) isknown to be resistant to traditional chemotherapy.Evidently, HNSCC cell lines have an elevatedexpression of Bcl-XL [15]. Overexpression of Bcl-XL

protein was observed in more than 60% of humancolon cancers and correlated with resistance to bothionizing radiation and chemotherapy. Furthermore,the cisplatin (CDDP) resistant squamous cell carci-noma cell line, SCC-25/CDDP, was shown to expressmore Bcl-XL protein than its parental cell line.Surprisingly, Bcl-2 is not increased in these cells,indicating that resistance to CDDP results from thepreferential induction of Bcl-XL expression [16].Similarly, Itoh et al. [17] found that a twofoldinduction of Bcl-XL is observed in two oral squamouscarcinoma cell lines MIT8 and MIT16, which areresistant to Carboplatin (CBDCA), an analog ofcisplatin widely used for chemotherapy of cancers.Numerous other studies have shown that Bcl-XL

overexpression is correlatedwith drug resistance to awide range of anticancer drugs, such as methotrex-ate, 5-fluorouracil, doxorubicin, vincristine, andtaxol in multiple cancers such as breast cancer,prostate cancer, leukaemia, and glioblastoma.Second, forced expression of ectopic Bcl-XL con-

verted drug-sensitive cancer cells to be drug-resis-tant. Itoh et al. showed that one oral squamouscarcinoma cell line MIT7 was CBDCA sensitive.However, when stably transfected with HA taggedBcl-XL, these cells displayed remarkable resistance tonot only CBDCA, but also mitomycin C, actinomy-cin D, and etoposide [17]. A similar finding wasobserved inhumanmelanoma cell lineMel Juso. Thecells stably transfected with Bcl-XL showed at leasttwofold higher resistance to cisplatin treatment thanthe control cells [18]. Anelegant study invivo furtherstrengthened this causal effect. In this study, Liuet al. injected mouse mammary carcinoma SCK cellsstably transfected with either Bcl-XL or controlplasmid into the right and left mammary fat padsof the same mouse. After 10 d, these mice wereintraperitoneally injected with methotrexate or 5-fluorouracil for 3 or 4 d. Tumors derived from Bcl-XL

expressing SCK cells were resistant to both metho-trexate and 5-fluorouracil and continued to grow.In comparison, tumors derived from the controlregressed. As a result, the tumors derived from SCKcells transfected with Bcl-XL were significantly largerthan the control tumors [19]. Additionally, reducedexpression of Bax that antagonizes the antiapoptoticrole of Bcl-XL was consistently associated with poor

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responses to chemotherapy as well as poor prognosisof metastatic breast cancer patients. Third, inhibi-tionofBcl-XL sensitizes cancer cells to chemotherapyagents. For example, the treatment of CBDCA-resistant squamous carcinoma cell lines (MIT8 andMIT16) mentioned above with Bcl-XL antisenseoligos dramatically inhibited cell growth [17].The mechanism through which Bcl-XL confers

cancer drug resistance is not clear. It is known thatmany anticancer drugs disrupt the mitochondrialmembrane, resulting in cytochrome c release andthus activating apoptosis. Therefore, it is plausible topostulate that overexpression of Bcl-XL blocks cyto-chrome c release and hence promotes cell drugresistance and survival. In this sense, Bcl-XL

decreases anticancer drug efficacy by convertingthem from cytotoxic to cytostatic agents.

Bcl-XL As a Potential Chemotherapy orChemoprevention Target

As discussed previously, cancer cells express highlevels ofBcl-XL and thusare resistant to conventionalchemotherapy. Intuitively, if a drug specificallyinhibits the expression or the function of Bcl-XL, itwould be possible to sensitize cancer cells tochemotherapeutic agents or radiation. Moreover,because overexpression of Bcl-XL is a common traitof many cancers, such a drug would be able to targetmultiple cancers. In general, there are two strategiesto target Bcl-XL.One is to regulate its expression. Theother is to neutralize Bcl-XL with small molecules.Here, we discuss some potential chemotherapeuticagents that may be used for chemoprevention orchemotherapy in skin cancer.

Targeting Bcl-XL Expression

Antisense oligonucleotides are single strandnucleotides capable of hybridizing complementarytarget mRNAs and thus preventing their translationor targeting their degradation. An AS2 oligonucleo-tide targeting human Bcl-2 (oblimersen, G3139) hascompleted early clinical studies in different malig-nancies, demonstrating target inhibition specificityand antitumor activity, alone and in combinationwith cytotoxic drugs, and this agent is currentlyundergoing Phase III trials in combination withchemotherapy. Taylor et al. have selected a panel ofantisense oligos for repressing Bcl-XL expression.One sucholigo, ISIS 16009 (50-CTACGCTTTCCACG-CACAGT-30), targeting the translation initiationof Bcl-XL, was able to reduce the Bcl-XL mRNA toapproximately 5% of the control level. This oligosensitized human lung carcinoma cell line A549 andhuman keratinocytes (hKn) to UVA irradiationor cisplatinum, respectively, indicating a possibleapplication in cancer chemotherapy and in chemo-prevention of UVA induced skin cancer [12]. Thehuman melanoma cell line, Mel Juso, was also

sensitized to cisplatin when transfected with thisoligo. The apoptotic cells sharply increased from7.9% of control to 28.5% [18]. This oligo was alsotested in the colon cancer cell line Caco-2. In thisstudy, the combination of ISIS 16009 and 12Gyionizing radiation increased cell death by about300% compared to irradiated Caco-2 cells pretreatedwith a nonspecific oligo.Furthermore, several other antisense oligos in

combination with 5-fluorouracil were able toincrease apoptosis and reduce cell growth signifi-cantly. A very promising Bcl-2/Bcl-XL bispecificoligo, 4625, was able to decrease Bcl-XL expressionmarkedly, promoting apoptosis in tumor cells anddelaying tumorgrowth inaxenograftmodel of coloncancer [20]. This antisense oligonucleotide (50-AAGGCATCCCAGCCTCCGTT-30) matches exactlyto the 605–624 nt of the Bcl-2 mRNA and hashomology to the 687–706 nt of Bcl-XL mRNA withthree mismatches, corresponding to the þ573 orþ550 nucleotides downstream of the AUG codon ofthe Bcl-2 or Bcl-XL mRNA, respectively. As a result,this bispecific oligo can reduce both Bcl-2 and Bcl-XL

expression simultaneously. It has been shown toinduce apoptosis and inhibit growth of differenttumor types in vitro and in vivo, showing greatpromise cancer chemotherapy [21].Other compounds were also tested for their ability

to induce apoptosis by inhibiting Bcl-XL expression.Curcumin (diferuloylmethane) is a phenolic com-pound derived from the root of the plant Curcumalonga and commonly used to impart a yellow color tofood. It has been shown that treatment of humanBCCcellswith 50mMof curcumin for 24, 48, and72hled to a 30, 50, and 63% apoptotic response,respectively. Similarly, curcumin treatment enhanc-es keratinocyte apoptosis by reducing Bcl-XL expres-sion [22]. Consistently, studies inDU145 and LNCaPprostate cancer cells indicated that curcumin causesapoptosis by reducing Bcl-XL levels in these cells.Curcuminwas able to induce apoptosis in other cellslines such as erbB2-transformed NIH 3T3 cells,human kidney cancer 293, human colon HT-29,hepatoma HepG2 cells, and mouse sarcoma S180,although the involvement of Bcl-XL downregulationwas not examined. In addition, its potential inchemoprevention has been tested inmultiplemousemodels for carcinogenesis. Interestingly, both topi-cal anddietary administrationof curcumin inhibitedDMBA/TPA or and TPAþUVA induced skin carcino-genesis in several independent studies [22].Several histone deacetylase (HDAC) inhibitors can

also downregulate Bcl-XL. HDAC is implicated inmultiple biological processes such as cell differentia-tion and cell death. A novel HDAC inhibitor,FR901228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabi-cyclo-[8,7,6]-tricos-16-ene-3,6,9,19,22-pentanone],a.k.a.depsipeptide, is a cyclicpeptide. Itwasoriginally

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isolated from Chrombacterium violaceum. It possessespotent antitumor activity against human tumor celllines and, therefore, is being used to treat hemato-logic malignancies in clinical trials. In addition,FR901228 effectively induced apoptosis and inhib-ited theproliferationof small cell lung cancer (SCLC)cells in vitro by reducing Bcl-XL mRNA and proteinafter a 24 h treatment [23].AnotherHDAC inhibitor, sodiumbutyrate (NaB) is

promising as well. NaB is a four-carbon fatty acidproduced during the digestion of complex carbohy-drates in the gut lumen.Cao et al. treated twohumanmesothelioma cell lines, REN and I-45, which areknown to be refractory to conventional chemother-apy. They found amarked decrease in Bcl-XL proteinexpression in both cell lines after a 3 mM NaBtreatment for 3 h. Consequently, more than 30% ofboth cell types underwent apoptosis [24]. Addition-ally, other HDAC inhibitors such as trichostatin Aseemed to have the same effect on Bcl-XL. Afterhuman lungadenocarcinoma cells LT23were treatedwith 200 ng/mL trichostatin A for 16 h, the Bcl-XL

mRNA level was dramatically reduced.

Neutralizing Bcl-XL

The antiapoptotic function of Bcl-XL is primarilydependent upon interacting with the BH3 domainsof proapoptotic molecules, such as Bax/Bak. Theore-tically, smallmoleculesmimicking the BH3domainsof these proapoptotic molecules will be able to blockthe antiapoptotic function of Bcl-XL by directcompetition and physical exclusion. Indeed, asynthetic Bad BH3 peptide was able to induceapoptosis both in vitro and in vivo [25].Degterev et al. screened a library of 16 320

chemicals from ChemBridge Corporation (SanDiego, CA) through a high-throughput screeningassay and identified two classes of small-moleculeinhibitors of Bcl-XL, BH3I-1, andBH3I-2with an IC50

of 2.4 and 3.3 mmol/L, respectively. These twoinhibitors specifically blocked the interactionbetween Bcl-XL and BH3 containing proapoptoticmolecules [26].An independent group identified 500 potential

inhibitors using a structure-baseddatabase screeningof the National Cancer Institute’s 3-D database of206000 small molecules and natural products. Onesuch compound, BL-11 binds to the BH3 domain ofboth Bcl-2 and Bcl-XL and is a dual inhibitor of thesetwo antiapoptotic molecules. Consequently, BL-11induced apoptosis in a dose dependent manner inMDA-MB-231 and HL-60 cell lines [27].

SUMMARY

Skin cancer has become amajor health problem inthe United States, because the high incidence ofnonmelanoma skin cancer the highmortality rate ofmelanoma. Moreover, melanoma is refractory toconventional chemotherapy. Therefore, efficient

strategies are demanded for the prevention andtreatment of this disease.Compelling evidence has indicated that Bcl-XL

plays a critical role in skin carcinogenesis. In somecases, Bcl-XL seems to bemore important than Bcl-2.As discussed previously, its involvement in multiplestages of cancer, such as initiation, promotion andprogression, invasion and metastasis, makes it anideal target for both chemoprevention and che-motherapy of skin cancer. Indeed, both in vitro andin vivo studies have shown that inhibition of Bcl-XL

by different approaches is able to induce apoptosis incancer and to sensitize drug resistant cancer cells tochemotherapeutic agents.While the search formorespecific and more potent agents targeting Bcl-XL isstill under way, the current datamay have paved theway for clinic trials of these Bcl-XL inhibitors inmelanoma and for designing novel strategies ofchemoprevention of nonmelanoma skin cancer.

ACKNOWLEDGMENTS

This work is supported by NIH grants CA23074,CA40584, and CA27502 to GTB. We thank Dr. SallyDickinson for critical reading.Weare also grateful forthe administrative assistance of Ms. Anne Cione.

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