Introduction
Many extracellular stimuli are converted into
specific cellular responses through the activa-tion of mitogen-activated protein kinase(MAPK) signalling pathways. MAPKs are ser-ine/threonine protein kinases that canphoshorylate both cytoplasmic and nucleartargets.
1,2Four distinct subgroups within theMAP kinase superfamily have been de-
scribed: extracellular signal-regulated kinases(ERKs), c-jun N-terminal or stress-activatedprotein kinases (JNK/SAPK), ERK/big MAPkinase 1 (BMK1), and the p38 group of pro-tein kinases.
3The p38 group is in mammals
represented by four isoforms (p38 α, p38 β,
p38γand p38 δ) with overlapping but also dis-
tinct physiological roles.4Among them, p38 α
is the best characterized isoform. Recently, itwas observed that retinoids, cisplantin andalso other chemoterapeutic agents initiatecancer cell apoptosis through the activationof p38 MAP kinase. This finding connectscancer therapies previously considered to bemechanistically unrelated and raises the pos-sibility of developing anti-cancer agents thatRadiol Oncol 2006; 40(1): 51-6.
The role of p38 MAP kinase in cancer cell apoptosis
Metka Lenassi, Ana Plemenitaš
Institute of Biochemistry, Medical Faculty, University of Ljubljana, Slovenia
Background. Cellular behaviour in response to many extracellular stimuli is mediated through MAP kinase
signalling pathways. p38 MAP kinase that is represented in mammals by four isoforms ( p38 α, p38β, p38γ
and p38 δ) is one of the four main subgroups of MAP kinases. Recent studies show that p38 activation is
necessary for cancer cell death initiated by variety of anti-cancer agents. This finding connected cancer ther-apies previously considered to be mechanistically unrelated and raised the possibility of developing anti-can-cer agents that lack the side effects caused by events upstream of p38 MAPK. Many of the details of p38induced apoptosis still need to be elucidated. Since most of the past studies rely only on the cell culture mod-els, all the results have to be verified using in vivo models. Also very little is known about the role of p38mediated apoptosis on non-neoplastic cells in response to anti-cancer agents.Conclusion. Although p38 activation of cancer cell apoptosis is a very complex process, recent studies in-
dicate a good starting point for new strategies that would increase the efficiency and decrease the toxicity ofproven therapies. 
Key words: tumor cells, cultured; apoptosis; MAP kinase; antineoplastic agents
Received 28 February 2006
Accepted 8 March 2006
Correspondence to: Prof. Ana Plemenitaš, PhD,
Institute of Biochemistry, Medical Faculty, Universityof Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia;Phone: + 386 1 543 76 52; Fax: +386 1 543 76 41; E-mail: ana.plemenitas@mf.uni-lj.sireview
lack the side effects caused by events up-
stream of p38 MAPK.5The potential thera-
peutic value of p38 and the availability of spe-cific chemical inhibitors made these proteinkinases the subject of intensive studies dur-ing the past years.
1
The focus of this review will be to highlight
the characteristics and components of thep38 pathway, its role in cancer cell apoptosisand to indicate possible implications for can-cer therapy.
The p38 MAP kinase signalling pathway
p38 MAP cascade regulates a variety of cellu-
lar responses to environmental stress, pro-in-flammatory cytokines, lipopolysaccharide(LPS) and other signals and was first de-scribed in 1994.
6-8The cascade consists of
three conserved kinase modules that includeMAPK kinase, which activates MAPK kinasethat in turn activates MAPK, in our case p38(Figure 1). p38 MAPK responds to the signalby becoming rapidly activated by dual phos-phorylation of the Thr-Gly-Tyr (TGY) motif.
9
Four isoforms of the p38 family have beenidentified in mammals: p38 α(p38),
6-8 p38β,10
p38γ11and p38 δ,12which differ in their tissue
expression and affinity for upstream activa-tors and downstream effectors.
4Among
them, p38 αand p38 βshow a relatively broad
tissue expression in contrast to p38 γand
p38δthat are differentially expressed de-
pending on the tissue type.13A major contri-
bution to the studies of p38 αand p38 βiso-
forms is the availability of specific inhibitors,developed principally using 2,4,5-triaryl imi-dazoles as a template.
14
There are two main MAPKKs that are
known to activate p38, MKK315and MKK6.16
While MKK6 is a common activator of all p38isoforms, MKK3 is unable to activate p38 βde-
spite 80% homology between these two MKKs.In specific cell types also MKK4, an upstreamkinase of JNK, can aid in the activation ofp38αand p38 δ. In addition to activation with
upstream kinases there is also a MAPKK-inde-pendent mechanism of p38 activation involv-ing TAB1, with no known biological context.
3
The diverse range of MAPKKKs, upstream
activators of MKKs, is responsible for suscep-tibility of p38 to such a wide range of extracel-lular stimuli. This MAP3K includes TAK1,
17
ASK118DLK/MUK/ZPK, MLK2 and MEKK4.19
The upstream of MAPKKs are also low molec-ular weight GTP-binding proteins from theRho family and p21- activated kinases.
3
The MAP kinase activation is often tran-
sient under physiological conditions, beingdownregulated by dephosphorylation of vari-ous members of the MAP kinase pathway.The proteins responsible for that are differentdual-specificity phosphatases, all grouped inthe MAP kinase phosphatase (MKP) family.
20
Activated p38 MAP kinase regulates the
activity of a wide range of protein kinases(MAPKAPK2, MNK1, PRAK, MSK1), tran-scription factors (CHOP, p53, ATF-1/2/6,Sap1, MEF2, ELK1 and others) and some oth-er proteins, which then further regulate theactivity of their targets. This complicated net-work of interacting proteins is in conse-quence responsible for different cell activi-ties, like apoptosis, cell-cycle arrest, cytokineproduction, cell differentiation, cell senes-cence and tumour suppression.
3, 5Lenassi M and Plemenitaš A / p38 MAP kinase in cancer cell apoptosis 52
Radiol Oncol 2006; 40(1): 51-6.Figure 1. p38 MAP kinase signalling pathway (accord-
ing to reference 3).
The role of p38 in apoptosis in cancer cells
Apoptosis is an active form of cell death that
plays an essential role in eliminating damagedcells or cells with defects in key-regulatedprocesses such as growth.
21Once this highly
regulated process is triggered, the apoptoticprogram involves activation of a series of bio-chemical events that end with the release ofproteins from the mitochondria into the cyto-plasm and the nucleus.
22Not surprisingly, sev-
eral tumours emerge with mutations in genesconferring apoptosis resistance, allowing themto continue uncontrolled growth under, fornormal cells, pro-apoptotic conditions.
23
There are some evidence for pro-apoptotic
and anti-apoptotic role of p38 MAPKs, de-pending on the cell type and the stimuli.Overexpression of the active form of the p38activator MKK6 protects cardiac myocytesfrom β-adrenergic receptor-mediated apopto-
sis.
24Similarly, the early activation of p38 is
necessary and sufficient to protect Kym cellsfrom tumour necrosis factor- α-mediated
apoptosis,
25and expression of p38 βresults in
attenuated cell death induced by Fas ligandand UV light
26. The activation of p38 may al-
so protect through the down-regulation of theFas receptor expression.
27
Even more reports support the pro-apop-
totic role of p38, for example, p38 is a media-tor of apoptosis in neurons
28and cardiac
cells.29In other cell types, p38 activates apop-
tosis upon stimulation with tumour necrosisfactor- α
30, transforming growth factor- β31or
in response to oxidative stress.32The latter
was also demonstrated in the case of TRAILinduced apoptosis mediated by reactive oxy-gen species (ROS)-activated p38 MAP kinasefollowed by the caspase activation in HeLacells.
33Cells treated with betulinic acid, a se-
lective inhibitor of human melanoma, also in-duce apoptosis through the ROS mediatedp38 activation.
34
The mechanisms by which p38 contributes
to an enhanced pro-apoptotic response in-clude the phosphorylation and translocation
of proteins from the Bcl-2 family, which leadsto the release of cytochrome c from the mito-chondria,
32, 35the transforming growth fac-
tor-β-induced activation of caspase 836as well
as the regulation of membrane blebbing andnuclear condensation.
37At the transcription-
al level, expression of monoamine oxidase28
or growth arrest and DNA damage (GADD)-inducible genes
38have been shown to medi-
ate pro-apoptotic effects of p38. The impor-tance of p38 in apoptosis was also shown inthe study of apoptotic response in differentp38-deficient cells, like primary fibroblastsand immortalized cardiomyocytes and fibrob-lasts. All p38 deficient cells were more resist-ant to apoptosis induced by many differentstimuli. The reduced apoptosis correlatedwith down-regulation of the proapoptoticproteins Fas and Bax as well as enhanced ac-tivity of the ERK survival pathway.
39 
This opposing effects on apoptosis ob-
served for p38 probably reflect the multipleand complex activities of this signalling path-way, which acts on different targets at onceand thus can yield distinct overall effects de-pending on the cellular context. Similar op-posing effects were also found for the otherstress-activated protein kinase JNK.
37
p38, a convergence point in cancer therapy?
Recent studies show that the p38 MAP kinase
activation is necessary for cancer cell deathinitiated by various anti-cancer agents.Retinoids like 13- cisretinoic acid or all- trans
retionic acid (ATRA) initiate apoptosis inmedulloblastoma cell lines by phosphorylat-ing p38 MAPK through the induction of bonemorphogenetic protein 2 (BMP2).
40Another
syntetic retinoid CD437 induces apoptosis inovarian carcinoma cell culture also in p38 de-pendent way. The activated p38 phosphory-lates the transcription factor MEF-2, whichhas a proposed role in mitochondrial depolar-Lenassi M and Plemenitaš A / p38 MAP kinase in cancer cell apoptosis 53
Radiol Oncol 2006; 40(1): 51-6.
ization and apoptosis. In these cells ATRA
does not induce p38 cascade, suggesting adistinct upstream mechanism from the onedescribed for medulloblastoma.
41
Four chemotherapeutic agents were shown
to induce the p38 activation and mitotic cell-cycle arrest in HeLa human cervical carcino-ma cells by depolymerizing microtubules,(nocodazole, vincristine and vinblastine) orstabilizing them (taxol). The extent of apopto-sis in these cells is greater when induced by adirect activation of p38, because previouslymentioned chemotherapeutics activate pro-apoptotic as well as pro-survival pathways inHeLa cells, which results in less apoptosis.The activated p38 induces cell death by stim-ulating translocation of Bax from the cytosolto the mitochondria. On the other hand, thep21-activated kinase (PAK) mediates cell sur-vival by phosphorylating Bad, thereby in-hibiting its pro-apoptotic function.
42
The activation of p38 in several tumour
cell lines was also observed after the treat-ment with cisplatin, an inorganic heavy met-al coordination complex, and doxorubicin, aDNA intercalating agent.
43
Some anti-cancer agents utilize two dis-
tinctive MAPK signalling pathways for killingcells. Phytosphingosine simultaneouslydownregulates the ERK survival pathway,which is critical for the death receptor inde-pendent activation of caspase-8, and activatesp38 pathway, which is involved in the celldeath pathway through the mitochondrial ac-tivation.
35Another example is 2-metho-
xyestradiol (2-ME) apoptosis induction inprostate cancer cell line. A treatment with 2-ME leads to the p38 activation as well as JNK-mediated Bcl2 phosphorylation, which inacti-vates this anti-apoptotic protein.
44
All these reports support the role of p38
MAPK as the key component for the cancercell death after treating tumours with a vari-ety of anti-cancer agents. This finding con-nects cancer therapies previously consideredto be mechanistically unrelated and raises thepossibility of developing anti-cancer agents
with the lack of the side effects caused byevents upstream of p38 MAPK.
5
Still many of the details of p38 induced
apoptosis need to be elucidated. Since mostof the past studies rely only on the cell culturemodels, all the results have to be verified us-ing in vivo models. Also very little is knownabout the role of p38 mediated apoptosis onnon-neoplastic cells in response to anti-can-cer agents. The issue is also the drug resist-ance, therefore, more has to be learned abouthow tumours protect themselves from thepro-apoptotic activation of p38 MAPK. Thestudy made on 20 liver cancer specimensshows that both MKK6 and p38 protein levelsare lover in hepatocellular carcinoma tu-mours than adjacent non-neoplastic liver.This reduction of p38 levels could representan anti-apoptotic mechanism that providesgrowth advantage to tumour cells.
45
Conclusions
Although the p38 activation of cancer cell
apoptosis is a very complex process, recentstudies indicate a good starting point for newstrategies that would increase the efficiencyand decrease the toxicity of proven therapies.One possible way to improve the efficiencywould be by treating patients simultaneouslywith available p38-activating agents and an-tagonists of anti-apoptotic pathways, likePAK and ERK inhibitors. An alternative strat-egy would be to use combinations of p38-ac-tivating chemotherapeutics. 
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Slovenian abstracts 62
Radiol Oncol 2006; 40(1): 57-62.Radiol Oncol 2006; 40(1): 000-00.
Vloga p38 MAP kinaze pri apoptozi rakavih celic
Lenassi M, Plemenitaš A
Izhodišča. Odzivanje celic na številne zunajcelične signale poteka preko aktivacije MAP ki-
naznih signalnih poti. Ena od štirih glavnih podskupin MAP kinaz je p38 MAP kinaza, ki je prisesalcih prisotna v štirih izooblikah: p38 α, p38β, p38γin p38 δ. Nedavne raziskave so pokazale,
da je za aktivacijo apoptoze rakavih celic z različnimi kemoterapevtiki nujna aktivacija p38 ki-naze. To spoznanje je v eni točki povezalo poti delovanja raznolikih kemoterapevtikov ter s temnakazalo nove možnosti njihovega razvoja brez stranskih učinkov, ki jih sedaj povzročajo do-godki pred aktivacijo p38. Veliko podrobnosti o p38 posredovani apoptozi je potrebno še raz-jasniti. Dosedanja dognanja je potrebno preveriti v in vivo modelih, saj se ta sedaj nanašajo
predvsem na celične kulture. Malo je znanega tudi o vlogi p38 pri apoptozi nerakavih celic poaktivaciji s kemoterapevtiki.Zaključki. Čeprav je p38 posredovana aktivacija apoptoze rakavih celic zelo kompleksen proces,
novejše študije ponujajo dober začetek za razvoj novih kemoterapevtikov s povečano učinkovi-tostjo in zmanjšano toksičnostjo.