Abstract
The natural agent, 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione (HMDB), has been reported to have growth inhibitory effects on several human cancer cells. However, the role of HMDB in cervical cancer remains unclear. Herein, we found that HMDB dose- and time-dependently inhibited growth of HeLa cervical cancer cells, accompanied with G1 cell cycle arrest. HMDB decreased protein expression of cyclins D1/D3/E and cyclin-dependent kinases (CDKs) 2/4/6 and reciprocally increased mRNA and protein levels of CDK inhibitors (p15, p16, p21, and p27), thereby leading to the accumulation of hypophosphorylated retinoblastoma (Rb) protein. HMDB also triggered the accumulation of acidic vesicles and formation of microtubule-associated protein-light chain 3 (LC3), followed by increased expression of LC3 and Beclin-1 and decreased expression of p62, suggesting that HMDB triggered autophagy in HeLa cells. Meanwhile, suppression of the expression of survivin and Bcl-2 implied that HMDB-induced autophagy is tightly linked to apoptosis. Exploring the action mechanism, HMDB induced autophagy via the modulation of AMP-activated protein kinase (AMPK) and mTOR signaling pathway rather than the class III phosphatidylinositol 3-kinase pathway. These results suggest that HMDB inhibits HeLa cell growth by eliciting a G1 arrest through modulation of G1 cell cycle regulators and by concomitantly inducing autophagy through the mediation of AMPK-mTOR and Akt-mTOR pathways, and may be a promising antitumor agent against cervical cancer.
Highlights
Cervical cancer is one of the leading causes of gynecologic cancer death in women worldwide and approximately 500,000 new cervical cancer cases are deduced, contributing to 280,000 deaths each year [1]
Akt that negatively regulate TSC2 to release its inhibition on Rheb (Figure 5b). These results suggested that the activation of AMPK and inhibitory modification of Akt-mTORC-S6K signaling axis by HMDB may contribute to autophagic induction and growth inhibition in HeLa cells
A majority of cervical cancer patients have benefited from neoadjuvant chemotherapy together with concurrent chemotherapy and radiotherapy, the survival rate remains poor in cervical cancer patients with relapse or recurrence [27]
Summary
Cervical cancer is one of the leading causes of gynecologic cancer death in women worldwide and approximately 500,000 new cervical cancer cases are deduced, contributing to 280,000 deaths each year [1]. AsAsshsohwownnininFiFgiugurere3a3,a,uuppppeerrppaanneell,, wwee oobbsseerrvveedd tthhaatt HHMMDDBB iinndduucceeddaatitmime-ed-depeepnednednetnt incinrecaresaeseininthtehefofromrmataitoinonofofinintrtaracceelllululalarr vvaaccuuoolleess iinn HHeeLLaa cceellllss. ImImmmunuonflofuluoroersecsecennccee sstataiinniinngg ddiisscclloosseedd tthhaatt HHMMDDBB--ttrreeaatetedd HHeeLLaacceelllslsaacccocommmmodoadtaetdedthtehe acaqcuqiusiitsiiotinonofofnunummereorouusslalarrggee aauuttoopphhaaggiicc vvaaccuuoolleess iinn tthhee ccyyttoopplalassmm. HHMMDDBB--IInndduucceedd AAuuttoopphhaaggyy IIss LLiinnkkeedd ttoo tthhee MMeeddiiaattiioonn ooff AAMMPPKK//mmTTOORR aanndd AAkktt//mmTTOORR SSiiggnnaalliinngg. GHerMedDBthterigpgheorsepdhothryelapthioonsp/hacotriyvlaattiioonn/aocftiAvaMtiPoKn oref cAipMroPcKallryecaicpcroomcapllaynaiecdcowmipthantihede dwoiwthnrthegeudlaotwionnreogfuthlaetiopnhoospf htohreylpahtioosnphstoartyulsaetsioonf sRtaaptutsoer,s mofTORRapatnord, Sm6KTO(RmTaOndR dSo6Kwn(smtrTeaOmR sduobwstnrsattree)aimn asutibmsetr-aretela)teind ma atnimneer-.reHlaMteDdBmalasnonhear.dHanMiDnhBibaitlsooryheafdfecatnoninthhiebpithooryspehfoferyctlaotinonthoef phosphorylation of Akt that negatively regulate TSC2 to release its inhibition on Rheb (Figure 5b). These results suggested that the activation of AMPK and inhibitory modification of. Akt that negatively regulate TSC2 to release its inhibition on Rheb (Figure 5b) These results suggested that the activation of AMPK and inhibitory modification of Akt-mTORC-S6K signaling axis by HMDB may contribute to autophagic induction and growth inhibition in HeLa cells
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