Aqueous Extracts of Toona sinensis Leaves Inhibit Renal Carcinoma Cell Growth and Migration Through JAK2/stat3, Akt, MEK/ERK, and mTOR/HIF-2α Pathways.
Toona sinensis (TS) is a type of deciduous tree, which is distributed widely in Asia and used as a traditional herb medicine. Previously, we demonstrated that aqueous extracts of TS leaves (TSL-1) induce apoptosis in two clear types of human renal carcinoma cells (ccRCC) via mitochondria-dependent pathway. In this study, we further investigated the more detailed mechanism of TSL-1-induced antitumor effects on ccRCCs. TSL-1 treatment arrested ccRCC cells in G0/G1 phase through the decrease of cyclin D1, cyclin-dependent kinase (CDK)2, and CDK4 as well as induction of p53 and FOXO3a protein expressions. On the other hand, the inhibitory effects of TSL-1 on migration were also observed in 786-O and A-498 cells. Mechanically, we presented that TSL-1 could suppress cell cycle progression and motility via inhibiting the phosphorylation of JAK2/stat3, Akt, MEK/ERK, and mTOR in a concentration- and time-dependent manner. Moreover, we found that TSL-1 inhibited p21, HIF-2α, c-Myc, VEGF, and MMP9 protein expressions in both cell lines. In conclusion, these findings suggested that TS-induced apoptosis and its antimigration activity in ccRCC cells were accompanied by inactivation of several oncogenic pathways.
a Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan.|b Department of Anatomy , School of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan.
Yung-Chia
YC
Chen
a Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan.
Ling-Hui
LH
Chien
c Department of Cell Biology and Anatomy , College of Medicine, National Cheng-Kung University , Tainan , Taiwan.
Bu-Miin
BM
Huang
d Department of Food Science and Technology , Ta-Jen University , Ping Tung , Taiwan.
Yi-Chen
YC
Chia
a Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan.|e Department of pharmacology , School of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan.
Hui-Fen
HF
Chiu
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D016213:Cyclins / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D029582:Meliaceae / Q000737:chemistry*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D018515:Plant Leaves / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D000972:Antineoplastic Agents, Phytogenic; D051792:Basic Helix-Loop-Helix Proteins; D016213:Cyclins; D053614:Janus Kinase 2; D020930:MAP Kinase Kinase Kinases; D010936:Plant Extracts; D051057:Proto-Oncogene Proteins c-akt; D050796:STAT3 Transcription Factor; D058570:TOR Serine-Threonine Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1; C494086:STAT3 protein, human; C546842:MTOR protein, human; C507924:JAK2 protein, human