Genistein‐induced mitotic arrest of gastric cancer cells by downregulating KIF20A, a proteomics study

Abstract

Genistein exerts its anticarcinogenic effects by inducing G2/M arrest and apoptosis of cancer cells. However, the precise molecular mechanism of action of genistein has not been completely elucidated. In this study, we used quantitative proteomics to identify the genistein-induced protein alterations in gastric cancer cells and investigate the molecular mechanism responsible for the anti-cancer actions of genistein. Total 86 proteins were identified to be regulated by genistein, most of which were clustered into the regulation of cell division and G2/M transition, consistent with the anti-cancer effect of genistein. Many proteins including kinesin family proteins, TPX2, CDCA8, and CIT were identified for the first time to be regulated by genistein. Interestingly, five kinesin family proteins including KIF11, KIF20A, KIF22, KIF23, and CENPF were found to be simultaneously downregulated by genistein. Significantly decreased KIF20A was selected for further functional studies. The silencing of KIF20A inhibited cell viability and induced G2/M arrest, similar to the effects of genistein treatment in gastric cancer. And the silencing of KIF20A also increased cancer cell sensitivity to genistein inhibition, whereas overexpression of KIF20A markedly attenuated genistein-induced cell viability inhibition and G2/M arrest. These observations suggested that KIF20A played an important role in anti-cancer actions of genistein, and thus may be a potential molecular target for drug intervention of gastric cancer.

The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways

“…Kinesin, present in all eukaryotes, is a microtubule-dependent molecular motor protein family, plays several roles in cellular functions, including chromosome alignment, cytokinesis, and chromosome segregation [58]. KIF20A (kinesin family protein member) is involved in tumor growth and progression [59]. Recent study reported that KIF20A played an important role in anti-tumor activity of genistein, and introduced KIF20A as a potential target for drug intervention of gastric cancer [59].…”

“…KIF20A (kinesin family protein member) is involved in tumor growth and progression [59]. Recent study reported that KIF20A played an important role in anti-tumor activity of genistein, and introduced KIF20A as a potential target for drug intervention of gastric cancer [59]. It was also reported that microinjection of anti- KIF20A antibody caused multinucleation of Hela cells [60].…”

Genistein and Cancer: Current Status, Challenges, and Future Directions

“…In SGC-7901 cells treated with 40 mM genistein for 48 h, the expression of 86 proteins involved in the regulation of G2/M transition, cellular growth, and proliferation resulted modulated by genistein, with 49 being upregulated and 37 being downregulated. In particular, 4 kinesins [kinesin-like protein (KIF) 11, KIF20A, KIF22, and KIF23] and a KIF, centromere protein F (CENPF), were found to be significantly downregulated by genistein, with KIF20A playing an important role in genistein-induced mitotic arrest (121).…”

Oncogenic role of kinesin proteins and targeting kinesin therapy

“…2). To test the clinical efficacy of these kinesin inhibitors, three ongoing phase I and II clinical trials of Eg5 inhibitors ARRY-520 and Litronesib are currently being carried out for advanced cancer patients; after the phase I trials were completed, no further continuous clinical studies for AZD4877 and MK0731 have been carried out to date (10,11) KIF3A, KIF3B Kinesin-2 Oncogenesis and metastasis of breast cancer and renal cell carcinoma (12,13) KIF1B Kinesin-3 Related to metastasis of nervous system tumor (14) KIF14 Kinesin-3 Overexpression promotes the development of breast, lung and retinoblastoma tumors (15)(16)(17) KIF4A Kinesin-4 Oncogenesis of cervical cancer and non-small-cell lung cancer (18,19) KIF7 Kinesin-4 Oncogenesis and metastasis of multiple cancers (20,21) Eg5 ⁄ KIF11 Kinesin-5 Overexpresion promotes the developmemnt of multiple cancers MPHOSPH1 ⁄ KIF20B Overexpressed in cancers of the bladder and colorectal (9,22) MKLP1 ⁄ KIF23 Kinesin-6 Downregulation causes cytokinesis defect in tumor cells (23) MKLP2 ⁄ KIF20A Kinesin-6 Overexpressed in pancreatic ductaladenocarcinoma cells and downregulation inhibits the growth of gastric cancer cells (24,25) CENP-E ⁄ KIF10 Kinesin-7 Downregulation inhibits the growth of multiple cancer cells (26) MCAK ⁄ KIF2C Kinesin-13 Overexpressed in many kinds of cancers and linked to taxel resistance of tumor cells (27)(28)(29) KIF2A Kinesin-13 Upregulation promotes the development of squamous cell carcinoma of the tongue (30) HSET ⁄ KIFC1 Kinesin-14 Associated with brain metastasis of lung cancer (31) KIFC3 Kinesin-14 Upregulation causes docetaxel resistance in breast cancer cells (32) ( Table 2). (66,67) Some of these Eg5 inhibitors showed great efficacy in preclinical models of human solid tumors; (66)(67)(68)(69)…”