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High exogenous NO inhibits proliferation and induces apoptosis by targeting PI3K/AKT/mTOR and MEK/ERK pathways in hepatocellular carcinoma cells
Author(s) -
Liu Ling,
Chen Jingjing,
Cao Mengyao,
Huang Zile,
Li Ruifang,
Wang Jiangang
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.481.4
Subject(s) - pi3k/akt/mtor pathway , protein kinase b , apoptosis , mapk/erk pathway , chemistry , cancer research , ly294002 , kinase , cell growth , phosphorylation , mek inhibitor , microbiology and biotechnology , biochemistry , biology
PABA/NO (O 2 ‐ {2,4‐dinitro‐5‐[4‐(Nmethylamino)benzoyloxy]phenyl} 1‐(N,N‐dimethylamino) diazen‐1‐ium‐1,2‐diolate) has N‐methyl‐p‐ aminobenzoic acid bound via its carboxyl oxygen as a 5‐substituent on the 2,4‐dinitrophenyl ring, a diazeniumdiolate‐based NO‐donor prodrug through releasing exogenous nitric oxide at high concentrations to induce apoptosis in many tumor cell lines. In the present study, the effects of PABA/NO on hepatocellular carcinoma proliferation and apoptosis induction were investigated both in vitro and in vivo experiments. PABA/NO dramatically inhibited the cell growth and significantly induced apoptosis in a concentration‐dependent manner, accompanied by down‐regulation of Bcl‐2, up‐regulation of Bax, and activation of cleaved‐caspase‐9 and cleaved‐caspase‐3. PABA/NO attenuated the PI3K/AKT/mTOR pathway through decreasing phosphorylation of PI3K p85 at Tyr458, AKT at Ser473, mTOR at Ser2448 and p70S6K at Thr389 in SMMC7721 cells. In addition, LY294002 as a specific PI3 kinase inhibitor can aggravate PABA/NO‐induced cell apoptosis. Furthermore, PABA/NO repressed the MEK/ERK pathway through decrease phosphorylation of MEK at Ser217/221, ERK at Thr202/Tyr204, and p90RSK at Ser380 in PABA/NO‐treated cells. ERK inhibitor U0126 could greatly intensify the apoptotic effects on PABA/NO‐treated cells compared to PABA/NO single treatment. Additionally, H22 tumor‐bearing mice experiments demonstrated that PABA/NO exerted good antitumor effects via reducing tumor volume, tumor weight and decreasing the expression of CD34. Furthermore, PABA/NO treatment strongly inhibited the phosphorylation of PI3K/AKT/mTOR and MEK/ERK signaling pathways in H22 hepatocellular carcinoma tissues. Collectively, these data clearly demonstrated PABA/NO ‐induced apoptosis through inhibition of PI3K/Akt/mTOR and MEK/ERK pathway in hepatocellular carcinoma cells. Support or Funding Information This work was financially supported by the National Natural Science Foundation of China (No.81502627) and the Young Backbone Teachers Assistance Scheme of Henan Province Colleges and Universities (No.2016GGJS‐065) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .