Combination Of Cytokinin And Auxin Induces Apoptosis,Cell Cycle Arrest,and Blockage Of Apoptosis,Cell Cycle Arrest,and Blockage Of Akt Pathway In HeLa Cells

Plant cytokinins and auxins have recently been proposed as novel cancer therapies through different mechanisms; however, their combined use has not been investigated. Here, we showed for the first time that the cytokinin ortho-methoxytopolin-riboside (MeoTR) strongly inhibited proliferation of HeLa cells, and this effect was synergistically enhanced by auxin IAA, while IAA had no cytotoxicity. MeoTR activated intrinsic and extrinsic caspase-dependent pathway, and IAA potentiated this activation, and these effects were blocked by Z-VAD-FMK, a pan-specific-caspase-inhibitor. IAA augmented MeoTR-induced inhibition of Bcl-2 and survivin. IAA only decreased Bcl-2 expression. MeoTR downregulated p-PDK1, p-Akt and p-GSK-3β, and combined with IAA was more effective, despite its weak effect alone. LY294002, an Akt-inhibitor, could augment the inhibition of p-Akt by MeoTR and combination treatment. IAA and MeoTR increased proportion of cells in S phase, and combination treatment induced further increase. IAA and MeoTR treatment downregulated protein levels of cyclin A, CDK2, and p-CDK2, and upregulated protein levels of p21 and p27, and combination treatment enhanced these effects, so IAA IAA potentiates the inhibitory effect of MeoTR on HeLa cells by S-phase-arrest and downregulation of Bcl-2. Combination treatment with these two phytohormones may offer a new therapeutic option for malignant cervical cancer.