Oxymatrine induces apoptosis in human cervical cancer cells through guanine nucleotide depletion.
Oxymatrine is an alkaloid obtained primarily from Sophora roots and has been shown to show anticancer effects in various cancers. However, the cellular and molecular effects of this agent on cervical cancer have been poorly characterized. Here, we investigated the antitumor effect of oxymatrine on a human cervical cancer cell line (HeLa). Our results showed that application of oxymatrine significantly inhibited the cell growth and tumorigenesis in a dose-dependent manner and induced apoptosis through caspase-dependent pathways as determined using flow cytometry and TUNEL staining analysis. To define the proteins potentially related to the mechanisms of action, proteomic analysis was utilized to detect proteins altered by oxymatrine. As the downregulated gene, inosine monophosphate dehydrogenase type II (IMPDH2) was responsible for oxymatrine-induced mitochondrial-related apoptosis. Moreover, oxymatrine depleted intracellular guanosine 5'-triphosphate (GTP) levels by effective IMPDH inhibition. Functional analyses further showed that oxymatrine and tiazofurin, an inhibitor of IMPDH2, sensitized resistant HeLa/DDP cells to cisplatin. In addition, the expression of IMPDH2 in cervical cancer was significantly higher than that in the normal cervical epithelium. Taken together, these findings suggest that targeting of IMPDH2 by potential pharmacological inhibitors, oxymatrine in combination with chemotherapy, might be a promising means of overcoming chemoresistance in cervical cancer with high IMPDH2 expression, and may thus provide new insights into the mechanism of oxyamtrine-induced anticancer effects.
aEngineering Research Center of Biotherapy and Translational Medicine of Shaanxi Province Departments of bObstetrics and Gynaecology cPathology dDisease Prevention and Health Promotion eGeneral Surgery, Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, People's Republic of China.
Mu
M
Li
Bao-Shan
BS
Su
Li-Hua
LH
Chang
Qing
Q
Gao
Kun-Lun
KL
Chen
Peng
P
An
Chen
C
Huang
Jun
J
Yang
Zong-Fang
ZF
Li
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006150:Guanine Nucleotides / Q000378:metabolism*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018307:Neoplasms, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D011807:Quinolizines / Q000494:pharmacology*; D015398:Signal Transduction; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000093842:Matrines
D000470:Alkaloids; D000970:Antineoplastic Agents; D020169:Caspases; D006150:Guanine Nucleotides; D007168:IMP Dehydrogenase; D011807:Quinolizines; C037573:oxymatrine; D000093842:Matrines; C501687:IMPDH2 protein, human