Abstract
Current clinical challenges of prostate cancer management are to restrict tumor growth and prohibit metastasis. AICAR (5-aminoimidazole-4-carbox-amide-1-β-d-ribofuranoside), an AMP-activated protein kinase (AMPK) agonist, has demonstrated antitumor activities for several types of cancers. However, the activity of AICAR on the cell growth and metastasis of prostate cancer has not been extensively studied. Herein we examine the effects of AICAR on the cell growth and metastasis of prostate cancer cells. Cell growth was performed by MTT assay and soft agar assay; cell apoptosis was examined by Annexin V/propidium iodide (PI) staining and poly ADP ribose polymerase (PARP) cleavage western blot, while cell migration and invasion were evaluated by wound-healing assay and transwell assay respectively. Epithelial–mesenchymal transition (EMT)-related protein expression and AMPK/mTOR-dependent signaling axis were analyzed by western blot. In addition, we also tested the effect of AICAR on the chemosensitivity to docetaxel using MTT assay. Our results indicated that AICAR inhibits cell growth in prostate cancer cells, but not in non-cancerous prostate cells. In addition, our results demonstrated that AICAR induces apoptosis, attenuates transforming growth factor (TGF)-β-induced cell migration, invasion and EMT-related protein expression, and enhances the chemosensitivity to docetaxel in prostate cancer cells through regulating the AMPK/mTOR-dependent pathway. These findings support AICAR as a potential therapeutic agent for the treatment of prostate cancer.
Highlights
Prostate cancer is the most common cancer and the second leading cause of cancer-related death among men in the United States [1]
Several agents have been demonstrated to activate AMPK, including metformin and phenformin, which increase the AMP:ATP ratio, the nucleoside AICAR which is metabolized to an AMP mimetic, and A769662, which is a direct activator of AMPK [32]
Sauer et al demonstrated that AICAR induces apoptosis of DU-145 prostate cancer cells through the AMPK/mTOR-dependent signaling pathway [21]
Summary
Prostate cancer is the most common cancer and the second leading cause of cancer-related death among men in the United States [1]. A previous study indicated that AICAR inhibited the growth of androgen-independent (DU145, PC3) and androgen-sensitive (LNCaP) cells after four days of treatment [25]. A current study showed that AICAR induced AMPK-independent programmed necrosis in prostate cancer cells [26]. Data are represented as means ± SD of triplicate values and statistical significance was determined using the Student’s t-test (* p < 0.05; ** p < 0.01; *** p < 0.001). Own, AICAR exhibited synergistic effect with docetaxel treatment in prostate cancer cells. IhneardeadsitAioInC,AoRurreedxupceerdimtheneteaxlprreessuslitosnshoof wmeTdOtRhatnAd IMCYACR enhanced the expression of TSC1 and TSC2 (Figure 6B), whereas AICAR reduced the expression of mTOR and MYC as well as decreased the phosphorylation of p70S6K (Figure 6C) These results suggest that AICAR inhibits the growth of prostate cancer cells through an AMPK/mTOR-dependent spausagtwghewesltaltyahs(aFdtiAegcuIrCreeAas6ReDdi)n.thhiebiptshothsephgroorwyltahtioofnporfopst7a0teS6cKan(cFeirgcuerlels6tCh)r.oTuhgehsaenreAsMulPtsKs/umgTgOesRt -tdheapt eAnIdCeAntR pianthhiwbiatsyt(hFeiggurorew6thDo).f prostate cancer cells through an AMPK/mTOR-dependent pathway (Figure 6D). FC(iAgeu)llrpsehw6oe.srpEehfftoer-ceAtatoMefdPAKwIC,itAAhMRdPiofKfne,rt(ehBne)tATcoSMnCPc1eKna/ntmrdaTtTOioSRnC-s2doewfpaAesnICdexeAanRmt pifnoarethd2wbhay.yTwihnees2te2exRrpnvr1belsposrtio.onCsteaoltfles(cAwa)neprceehrtorcseepalhtleso.dCAcwAcwbw(TaoeDMoalnnhMailosntld)cesPtshcetPdPKeipdwnwdnKern7e,totigeer,tfet0AprasfreArSearteotrMmee6ritMmsoeitrsKeoiPrnnnuniPdennKtslweaKstbemcd,ostdal,ooe(foesBa(dnbfAtBbcryc)Atdheywi)eITneCaIwnTrCitwSgnttAeeSeCrhAipreCassrRm1setrmRtd1etiesfaoeiirsuofanfornnnoefrnlnefedsntrdd6bsrtto6behTlahoaTflbnethSo.rtiASytC.v.tea(C.C(cIenAw2CCroA2t)ecowneiA)cTwcptfscTitaaRhrtneiarhnesenenesfrsecweostneweeerxuerxanraxaxbalps6ttatempsliasrmfoouhrtefuitnioe.esnsiv.secnsbs(seeeCstdAitedsodoiad)oocnfaiibnTntnafsbAiyosehdnryoafdIeeuwafCwmwslcemiouleAenxaoTesaldTpsRsattOdtsetOdrhbueierRfnioyrrRnsosn,negebsr,gAcebidtcobcM2alIcMsoonlaCiooehnYntsoYA.pnt.etC.faCrtaCdTRCro,mreloh,paleoiilpleTnnltlhiaselnhiOsoden2twoexshR2iwwsnpxwpRer,pepegherrcvehsreeeeoMs1cetosrrettossire-prtYrmienp-rernorpCepnta7oenra7a,tb0snoetb0prStloetldoaSals6hdfoittt.Knowe.et(Kw.(AsTDciwapeTtiaah)nxhth)hnenheppdoesPcddhertwdepriew-roprfiop7ireffsm7epnce70fspe0sert0SoehertbSelS6selenrno6ls6eKrnnot.K-tdKnstt.. bmloetctihnagnirsemsuoltfsthareearnetpicraensecenrtaetfifveectosfinrdesuucletds obbytAaiInCeAd Rininth2r2eRevs1epparorastteateexcpaenrciemrecnetlsls..(D) Proposed mechanism of the anticancer effects induced by AICAR in 22Rv1 prostate cancer cells
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