TMPYP4 exerted antitumor effects in human cervical cancer cells through activation of p38 mitogen activated protein kinase

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1 Cheng nd Co Biol Res (27) 5:24 DOI.86/s Biologicl Reserch RESEARCH ARTICLE Open Access TMPYP4 exerted ntitumor effects in humn cervicl cncer cells through ctivtion of p38 mitogen ctivted protein kinse Ming Jun Cheng nd Yun Gui Co * Astrct Bckground: The im of the present study ws to investigte the potentil effects of the 5,,5,2-tetrkis (-methylpyridinium-4-yl) porphyrin (TMPyP4) on the prolifertion nd poptosis of humn cervicl cncer cells nd the underlying mechnisms y which TMPyP4 exerted its ctions. Results: After humn cervicl cncer cells were treted with different doses of TMPyP4, cell viility ws determined y 3-(4,5-dimethyl-2-thizolyl)-2,5-diphenyl-2-H-tetrzolium romide (MTT) method, the poptosis ws oserved y flow cytometry (FCM), nd the expression of p38 mitogen-ctivted protein kinse (MAPK), phosphted p38 MAPK (p-p38 MAPK), cpse-3, MAPKAPK2 (MK-2) nd poly ADP-riose polymerse (PARP) ws mesured y Western lot nlysis. The nlysis reveled tht TMPyP4 potently suppressed cell viility nd induced the poptosis of humn cervicl cncer cells in dose-dependent mnner. In ddition, the up-regultion of p-p38 MAPK expression levels ws detected in TMPyP4-treted humn cervicl cncer cells. However, followed y the lock of p38 MAPK signling pthwy using the inhiitor SB2358, the effects of TMPyP4 on prolifertion nd poptosis of humn cervicl cncer cells were significntly chnged. Conclusions: It ws indicted tht TMPyP4-inhiited prolifertion nd -induced poptosis in humn cervicl cncer cells ws ccompnied y ctivting the p38 MAPK signling pthwy. Tken together, our study demonstrtes tht TMPyP4 my represent potentil therpeutic method for the tretment of cervicl crcinom. Keywords: TMPyP4, p38 MAPK, Humn cervicl cncer cells, Prolifertion, Apoptosis Bckground Cervicl cncer is the fourth common mlignnt tumor in women which leds to pproximtely 274, mortlities every yer worldwide ccording to the reports of the World Helth Orgniztion (WHO) []. Notly, 85% of cses nd deths occur in low- nd middle-income countries [2]. Humn ppillomvirus (HPV) types is recognized s n essentil precursor to the development of cervicl cncer. The WHO hs recommended the routine HPV vccintion in ntionl immuniztion progrmmes *Correspondence: yunguico@sin.com Deprtment of Gynecology, Shnghi Jiding District Mternl nd Child Cre Hospitl, No. 26, Goti Rod, Jiding District, Shnghi 282, Chin worldwide. Erly stge cervicl cncer my e treted y triggering tumor cell poptosis through the comined ppliction of rdiotherpy nd chemotherpy [3]. However, ptients with lte-stge cervicl cncer exhiit poor physicl condition, resulting in the limits of the ppliction of rdiotherpy, chemotherpy or the two therpies comined [4]. Currently, the pthogenesis of cervicl cncer hs not yet een completely understood, nd there re no drugs ville for effectively controlling the occurrence nd development of this cncer [5]. So, it is urgent for us to seek new potentil drugs nd iomrkers for its dignosis, prognosis, nd therpy to improve clinicl strtegies of cervicl cncer. The Author(s) 27. This rticle is distriuted under the terms of the Cretive Commons Attriution 4. Interntionl License ( which permits unrestricted use, distriution, nd reproduction in ny medium, provided you give pproprite credit to the originl uthor(s) nd the source, provide link to the Cretive Commons license, nd indicte if chnges were mde. The Cretive Commons Pulic Domin Dediction wiver ( pulicdomin/zero/./) pplies to the dt mde ville in this rticle, unless otherwise stted.

2 Cheng nd Co Biol Res (27) 5:24 Pge 2 of 7 The ctionic porphyrin, 5,,5,2-tetr-(N-methyl-4- pyridyl) porphine (TMPyP4), novel type of synthetic wter-solule photosensitizer, hs een recently developed s chemotherpeutics drug for treting cncers [6]. It hs een reported tht TMPyP4 leds to the rrest of tumor cell growth, nd induces the poptosis of tumor cells through reducing the telomerse ctivity [7 9], indicting tht TMPyP4 presents potentil therpeutic trget in tumor cells. Therefore, it is crucil to comprehensively understnd iologicl effects of TMPyP4 in tumor cells efore it cn e used for nti-cncer therpeutics. In the present study, we evluted the effects of TMPyP4 on the prolifertion nd poptosis of humn cervicl cncer cells nd further explored its underlying mechnisms. Methods Cell culture Humn cervicl cncer cell line Hel nd humn norml cervicl cells (Acdemi Sinic Cell Bnk, Shnghi, Chin) were grown in low-glucose Dulecco s modified Egle medium (GicoBRL, Grnd Islnd, NY, USA) supplemented with % (v/v) fetl ovine serum (Sigm- Aldrich Chemicls, USA), IU/mL penicillin, nd mg/ml streptomycin. Cells were cultured in incutor with 5% CO 2 t 37 C. Cell viility ssy Cell viility ws ssessed using MTT ssy (Bestio Biotechnology, Shnghi, Chin). Briefly, fresh humn cervicl cncer cells nd humn norml cervicl cells t concentrtion of 5 3 cells/well were seeded in 96-well flt-ottomed tissue culture pltes (Corning Inc., Corning, NY, USA) with complete culture medium nd incuted for 24 h. Following two wshes with phosphte-uffered sline (PBS), cells were incuted in μl culture medium contining, 5, or 2 μm TMPyP4 for 24 h t 37 C prior to the MTT ssy. Then, totl of μl MTT nd μl culture medium ws dded to ech well, nd incuted for h t 37 C. The opticl densities of the smples were mesured directly using spectrophotometric microplte reder (Beyotime Institute of Biotechnology, Himen, Chin) t wvelength of 49 nm. Ech experiment ws performed in triplicte nd repeted six times. Cell poptosis ssy The poptotic cells were identified y FCM ccording to the pulished rticle []. Humn cervicl cncer cells nd humn norml cervicl cells t density of 2 4 / ml were cultured in % FBS-contining DMEM with, 5, or 2 μm TMPyP4 for 24 h, respectively. Cells were hrvested nd wshed twice with cold PBS y gentle shking. Resuspended cells were dded to inding uffer nd cell density ws djusted to 2, 5,/ ml. In the drk, 5 μl of Annexin V-FITC (5 mm TRIS, mm NCl, % BSA,.2% sodium zide, ph 7.4) ws dded to the cell suspension in mix of 95 μl nd incuted for min t room temperture efore dding 9 μl inding uffer nd μl propidium iodide (PI). Cell poptosis ws ssyed using FACScn flow cytometry pprtus (BD Biosciences, Sn Jose, CA, USA) nd the percentge of poptotic cells ws nlyzed using FlowJo 7.6. softwre (TreeStr, Inc., Ashlnd, OR, USA). Ech experiment ws performed in triplicte nd repeted six times. Western lot nlysis Following the tretment with 2 μm TMPyP4 for 24 h, cells were collected for protein extrction. The exmintion of the expression levels of cspse-3, MK-2, PARP, p38 MAPK nd p-p38 MAPK ws then performed. Totl protein ws extrcted nd the icinchoninic cid ssy kit (Beyotime Institute of Biotechnology) ws used to mesure the protein concentrtion. A totl of 2 μg protein ws seprted y SDS-PAGE nd trnsferred onto polyvinylidene fluoride memrne using wet trnsfer pprtus (Bio-Rd, Hercules, CA, USA). The memrnes were then locked with 5% skimmed milk nd incuted overnight t 4 C with the primry ntiodies, followed y incution with the secondry ntiodies leled with HRP. Next, the protein nds were visulized using n enhnced chemiluminescence kit (Millipore, Billeric, MA, USA) nd the protein levels were detected using the chemiluminescence reder, ImgeQunt LAS4 (GE Helthcre, Pittsurgh, PA, USA). Antiodies were purchsed from Snt Cruz Biotechnology, CA, USA. Bnd density ws quntitted using Imge J softwre (Imge J.35, Ntionl Institute of Mentl Helth, USA). Cspse 3 ctivity ssy Cspse-3 ctivity ws nlyzed using cspse-3 ctivity ssy kits ccording to the mnufcturer s instructions. Briefly, the rection uffer nd the specific enzyme DEVD-pNA were dded to ech cell plte nd further cultured in n incutor for h t 37 C. The developed colorimetric rection ws mesured t 45 nm in 96-well Biord 68 microplte reder (Bio-Rd, Hercules, CA, USA). Block of p38 MAPK signling using inhiitor Cells were treted with p38 MAPK inhiitor SB2358 (5 μm) for 24 h followed y ddition of 2 μm TMPyP4, nd further incuted for 24 h. Then, cell prolifertion nd poptosis were evluted.

3 Cheng nd Co Biol Res (27) 5:24 Pge 3 of 7 Sttisticl nlysis All results were nlyzed using SPSS 7. sttisticl softwre (IBM, Armonk, NY, USA). Dt re presented s the men ± stndrd devition (SD). Student s two-tiled t test ws used to determine the sttisticl differences etween the tretment nd control groups. P vlues were sed on the two sided sttisticl nlysis, nd P <.5 ws considered to indicte sttisticlly significnt difference. Results TMPyP4 inhiited the prolifertion rtes of humn cervicl cncer cells To investigte the roles of TMPyP4 in humn cervicl cncer cells, we performed the MTT ssy to evlute the chnges of cell viility. It ws found tht TMPyP4 (IC 5 = 6.35 μm) significntly decresed OD 49 vlues of humn cervicl cncer cells in dose-dependent mnner compred with the control group without TMPyP4 tretment (P <.5) (Fig. ). On the other hnd, OD 49 vlues OD 49 OD Fig. TMPyP4 inhiited cell prolifertion in humn cervicl cncer cells. After cells were treted with, 5, or 2 μm TMPyP4 for 24 h, cell prolifertion in humn cervicl cncer cells () nd humn norml cervicl cells () ws mesured y MTT ssy. Dt re expressed s men ± SD of three independent experiments in six replictes. *P <.5 or P <. indictes significnce, P >.5 mens no difference of humn norml cervicl cells were minimlly ffected fter exposed to TMPyP4 t different concentrtions (P >.5) (Fig. ). These results indicted tht TMPyP4 hd low cytotoxic effects on humn norml cells nd inhiited cell prolifertion in humn cervicl cncer cells. TMPyP4 induced the poptosis of humn cervicl cncer cells To evlute the poptotic effects of TMPyP4 on humn cervicl cncer cells, cells were respectively exposed to different concentrtions of TMPyP4 for 24 h. As shown in Fig. 2, TMPyP4 remrkly induced the poptosis of humn cervicl cncer cells in dose-dependent mnner. Approximtely 9., 5., 36, 55.% of cncer cells occurred poptosis respectively fter exposed to, 5,, 2 μm TMPyP4 for 24 h, ut less thn 6.% of cncer cells without TMPyP4 stimultion showed poptosis. Next, to further scertin the poptotic effects of TMPyP4 on humn cervicl cncer cells, typicl poptotic mrker cspse-3 ctivity ws mesured y commercil kits. As shown in Fig. 2, cspse-3 ctivity ws promoted in TMPyP4-treted humn cervicl cncer cells (P <.5), which indicted tht TMPyP4 indeed triggered poptosis in humn cervicl cncer cells. Nevertheless, results in Fig. 2c provided the evidence tht there ws no significnt poptosis in humn norml cervicl cells fter eing exposed to the indicted concentrtion of TMPyP4 for 24 h (P >.5). These findings suggested tht TMPyP4 oviously induced poptosis in humn cervicl cncer cells, ut not in humn norml cervicl cells. TMPyP4 ctivted p38 MAPK signling in humn cervicl cncer cells To determine the mechnisms underlying the promotion of cell poptosis, we ssessed the expression pttern of p38 MAPK signling components including p38 MAPK nd p-p38 MAPK y Western lot ssy in humn norml cervicl cells nd humn cervicl cncer cells (Fig. 3). Western lot nlysis of p38 MAPK found tht p38 MAPK protein ws expressed in humn cervicl cncer cells nd humn cervicl cncer cells, ut it showed no difference etween TMPyP4 (2 μm) treted cells nd non-tmpyp4 treted cells (P >.5). Furthermore, there ws no ovious chnges in protein expression of p-p38 MAPK etween TMPyP4-treted norml cells nd the control norml cells (P >.5). In contrst, the p-p38 MAPK expression level ws comprtively low in humn cervicl cncer cells compred with norml cells, nd elevted protein level of p-p38 MAPK ws demonstrted in TMPyP4-treted cells in comprison with cncer cells without TMPyP4 stimultion (P <.5) (Fig. 3). It ws suggested tht TMPyP4 could ctivte the p38 MAPK signling pthwy in humn cervicl cncer cells.

4 Cheng nd Co Biol Res (27) 5:24 Pge 4 of 7 6 Norml cells Norml cells (TMPyP4 ) Tumor cells Tumor cells (TMPyP4 ) 5 p38 MAPK Cell poptotic rtes(%) Cspse-3 ctivity Cell poptotic rtes(%) c * Activtion of p38 MAPK signling in humn cervicl cncer cells is required for TMPyP4 induced down regultion of cell viility Further, we exmined the influence of p38 MAPK signling on TMPyP4-induced down-regultion of cell viility in humn cervicl cncer cells. Cells treted with p38 MAPK signling inhiitor SB2358 showed decline 5 2 * Fig. 2 TMPyP4 induced cell poptosis in humn cervicl cncer cells. Humn cervicl cncer cells were treted with, 5, or 2 μm TMPyP4 for 24 h, the poptotic rtes (), nd cspse-3 ctivity () in cells ws determined. The poptotic rtes of humn norml cervicl cells treted with, 5, or 2 μm TMPyP4 for 24 h were tested y FCM (c). Dt re expressed s men ± SD of three independent experiments in six replictes. *P <.5 or P <. indictes significnce, P >.5 mens no difference p-p38 MAPK -ctin Norml cells Norml cells.9 Tumor cells TMPyP4.8 Tumor cells TMPyP p38 MAPK p-p38 MAPK Fig. 3 TMPyP4 ctivted the p38 MAPK signling pthwy in humn cervicl cncer cells. Humn cervicl cncer cells or humn norml cervicl cells were treted with 2 μm TMPyP4 for 24 h, the protein expression level of p38 MAPK nd p-p38 MAPK ws mesured y Western lot (). Bnd density ws nlyzed using Imge J softwre (). Dt re expressed s men ± SD of three independent experiments in triplicte. *P <.5 or P <. indictes significnce, P >.5 mens no difference Reltive intensity nd rtio in MK-2 protein expression, ut hd no effects on p-p38 MAPK expression compred to the control cells (Fig. 4), suggesting etter inhiitory efficiency of SB2358. Cell viility ws promoted showing s high OD 49 vlues in SB2358-treted cells while it ws inhiited in TMPyP4-treted cells compred to the control (P <.5). However, there ws no difference in cell OD 49 vlues etween SB2358-TMPyP4 co-treted cells nd SB2358 treted cells (P >.5) (Fig. 4). Activtion of p38 MAPK signling in humn cervicl cncer cells is required for TMPyP4 triggered poptosis To further confirm whether p38 MAPK ctivtion contriuted to TMPyP4-triggered poptosis in humn cervicl cncer cells, phrmcologicl inhiitor of p38 MAPK, SB2358 ws used in this study. It ws found tht pretretment of 5 μm SB2358 remrkly ttenuted the poptotic rte (Fig. 5) nd cspse-3 ctivity (Fig. 5), while TMPyP4 significntly induced poptosis y promoting the poptotic rte, cspse-3 ctivity, nd PARP nd cspse-3 protein expression (Fig. 5c) in humn cervicl cncer cells (P <.5). Moreover, the poptotic rte, cspse-3 ctivity, cspse-3 nd

5 Cheng nd Co Biol Res (27) 5:24 Pge 5 of Cell poptotic rtes(%) Control TMPyP4 SB2358 TMPyP4+SB OD Cspse-3 ctivity Control TMPyP4 SB2358 TMPyP4+SB Control TMPyP4 SB2358 TMPyP4+SB2358 Fig. 4 The p38 MAPK signling pthwy ws involved in TMPyP4- inhiited cell prolifertion in humn cervicl cncer cells. Cells were seeded in 6-well pltes for 48 h nd then treted with SB2358 in humn cervicl cncer cells for 24 h, Western lot ws performed to determine protein expression of p-p38 MAPK nd MK-2 for evluting the locking efficiency of SB2358 (). Cells were treted with SB2358 for 24 h, nd 2 μm TMPyP4 ws dded for 24 h, then cell viility ws determined y MTT method (). Dt re expressed s men ± SD of three independent experiments in six replictes. *P <.5 or P <. indictes significnce, P >.5 mens no difference PARP protein expression showed no difference etween SB2358-treted cells nd SB2358-TMPyP4 cotreted groups (P >.5). These results indicted tht p38 MAPK ctivtion ws involved in TMPyP4-induced poptosis in humn cervicl cncer cells. Discussion TMPyP4, serving s photosensitizer in PDT, hs proved to ply n essentil role in controlling osteosrcom []. Besides, TMPyP4 hs een recently developed s chemotherpeutics drug to inhiit telomerse ctivity through c Reltive intensity nd rtio Cspse-3 PARP ctin Control Cspse-3 SB2358 Control TMPyP4 TMPyP4+ TMPyP4 SB2358 PARP SB2358 TMPyP4+SB2358 Fig. 5 The p38 MAPK signling pthwy ws involved in TMPyP4- triggered cell poptosis in humn cervicl cncer cells. Cells were treted with SB2358 for 24 h, nd 2 μm TMPyP4 ws dded for 24 h, then cell poptotic rtes (), cspse-3 ctivity (), PARP nd cspse-3 protein expression (c) were mesured. Dt re expressed s men ± SD of three independent experiments in six replictes. *P <.5 or P <. indictes significnce, P >.5 mens no difference inding to nd stilizing telomeric G-qudruplex DNA in cncer cells [7 9]. Through directly interction with telomeres, TMPyP4 cn rpidly evoke ntiprolifertive

6 Cheng nd Co Biol Res (27) 5:24 Pge 6 of 7 effects [2]. In vivo, fter intrtumor injection of mg/ kg TMPyP4 for dys, cervicl tumor growth in nude mice ws significntly inhiited without ny injury to the skin nd internl orgns [3]. Therefore, in this study, we used this gent for investigtion in cultured humn cervicl cncer cells to further evlute its ntitumor effects nd underlying mechnism. In the present study, tretment with vrious concentrtion of TMPyP4 significntly induced inhiition of prolifertion in humn cervicl cncer cells. Previous report suggested tht TMPyP4 could led to progressive telomere shortening tht eventully resulted in cncer cell poptosis [6]. Mikmi-Tero et l. ever demonstrted tht tretment with μm TMPyP4 significntly inhiited the growth of K562 leukemic cells, with decreses of cells in the G() phse nd increses of those in the S nd G(2)/M phses fter 48 h [4]. In the following study, Mikmi-Tero nd his tem found tht TMPyP4 t doses of, 2, 5 or μm significntly inhiited the growth of retinolstom cell lines, Y79 nd WERI-R cells. In contrst, cell poptosis ws induced y TMPyP4 in dose-dependent mnner in oth cell lines, which ws ssocited with the incresed expression of phosphorylted p53 (Ser46) protein nd ctivtion of MAPK [5]. TMPyP4 t concentrtions of 3, 6, 5, 3 or 6 μm significntly inhiited the prolifertion nd motility of humn ovrin crcinom A278 cells ut suppressed the expression levels of minichromosome mintennce protein-2 (MCM2) nd cronic nhydrse IX (CA-IX) [6]. Additionlly, TMPyP4 inhiited prolifertion while induced poptosis in colon cncer cells SW48 y the suppression of Wnt/β-ctenin signling pthwy [7]. More recently, study demonstrted tht, TMPyP4 t low doses less thn.5 μm could promote the migrtion of humn lung cncer A549 cells, HeL, osteosrcom U2OS nd SAOS2. In contrst, TMPyP4 t high-dose lrger thn 2 μm inhiited cell prolifertion nd induced cell poptosis in these cells [8]. These findings ove provided new insights into TMPyP4 which could e developed s possile nticncer drug. Numerous studies hve indicted tht the mitogenctivted protein kinse (MAPK) signling pthwy plys n importnt role in regulting cell prolifertion, promoting cell cycle progression [9 2], nd inducing resistnce to rdiotherpy nd chemotherpy in tumor cells [22, 23]. In ddition, p38 MAPK signling cscde is mjor pthwy prticipting in the poptotic pthwy to suppress poptosis of tumor cells [24, 25]. For instnce, K562 leukemic cells treted with μm TMPyP4 showed decrese in c-myc protein expression, nd n ovious increse in the expression of p2 (CIP), p57 (KIP2), p38 MAPK, c-jun N-terminl kinse, nd extrcellulr signl-regulted kinse [4]. Most interestingly, our dt showed tht TMPyP4 could promote the expression level of p-p38 MAPK in humn cervicl cncer cells, implicting p38 MAPK ctivtion s potentil trget for TMPyP4. Also, we provided the evidence tht the p38 MAPK signling ws involved in TMPyP4-indcued chnges in prolifertion nd poptosis of humn cervicl cncer cells. Conclusions In conclusion, we not only reveled criticl role for TMPyP4 in humn cervicl cncer cell prolifertion nd poptosis, ut lso explored the moleculr mechnisms y which TMPyP4 contriuted to its ntitumor effects. Up-regultion of the p38 MAPK signling pthwy y TMPyP4 could inhiit cell prolifertion while promoted cell poptosis in humn cervicl cncer cells. This study provided insight into the moleculr mechnism of the ntitumor effects of TMPyP4, indicting the p38 MAPK signling might e potentil therpeutic trget for TMPyP4 in humn cervicl cncer. Authors contriutions CYG ws the gurntor of integrity of the entire study nd ws responsile for mnuscript review. CMJ designed this study nd took experimentl studies. Both uthors red nd pproved the finl mnuscript. Competing interests The uthors declre tht they hve no competing interests. Avilility of dt nd mterils The dtsets used nd/or nlysed during the current study re ville from the corresponding uthor on resonle request. Funding This rticle ws supported y the grnts from the Ntionl Nturl Science Foundtion of Chin (The reserch on Rc -regulted ESCs functions during wound heling, Grnt No.: 83639) nd Chongqing Science nd Technology Project (Grnt No.: cstc23jcyja38). Pulisher s Note Springer Nture remins neutrl with regrd to jurisdictionl clims in pulished mps nd institutionl ffilitions. Received: 3 Mrch 27 Accepted: 2 June 27 References. Crosie EJ, Einstein MH, Frnceschi S, Kitchener HC. Humn ppillomvirus nd cervicl cncer. Lncet. 23;382: Cmpos NG, Shrm M, Clrk A, Kim JJ, Resch SC. Resources required for cervicl cncer prevention in low- nd middle-income countries. PLoS ONE. 26;():e Aryn M, Cstellsgué X, de Snjosé S, Bruni L, Sriy M, Bry F. Worldwide urden of cervicl cncer in 28. Ann Oncol. 2;22(2): Kodm J, Seki N, Mshiro S, Kusumoto T, Nkmur K, Hongo A, Hirmtsu Y. Prognostic fctors in stge IB IIB cervicl denocrcinom ptients treted with rdicl hysterectomy nd pelvic lymphdenectomy. J Surg Oncol. 2;:43 7.

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