Protein kinase B

Biology

P70-S6 Kinase 1

Kinase

Molecular biology

Apoptosis

Chemistry

Cell cycle

Ribosomal s6 kinase

p38 mitogen-activated protein kinases

Ribosomal protein s6

Signal transduction

Cell biology

Protein kinase A

Cancer research

Biochemistry

PI3K/AKT/mTOR pathway

Molecular Medicine Reports

Paclitaxel is a diterpenoid compound, derived from the pacific yew (Taxus brevifolia) berry, which exhibits antineoplastic effects against various types of cancer. However, the antitumor effects and the molecular mechanisms of paclitaxel on canine CHMm cells remain to be elucidated. The aim of the present study was to investigate the antitumor effects of paclitaxel on CHMm cells and identify relevant signal transduction pathways modulated by paclitaxel using multiple methods including MTT assay, flow cytometry, acridine orange/ethidium bromide staining, transmission electron microscopy, determination of cellular reactive oxygen species (ROS), superoxide dismutase (SOD) and malondiadehyde (MDA) and western blotting, the data indicated that paclitaxel decreased cell viability, induced G2/M‑phase cell cycle arrest, suppressed the expression of cyclin B1 and induced apoptosis in a dose‑dependent manner. In addition, paclitaxel upregulated the expression of Bax and cytochrome c, but reduced expression of apoptosis regulator Bcl‑2, resulting in activation of caspase‑3, chromatin condensation, karyopyknosis, intracellular vacuolization, increased production of ROS and MDA, and decreased activity of SOD. However, these effects were inhibited when CHMm cells were treated with N‑acetyl‑L‑cysteine. Furthermore, treatment with paclitaxel inhibited the level of of phospho (p)‑RAC‑α serine/threonine‑protein kinase (AKT) and p‑ribosomal protein S6 kinase proteins, and promoted phosphorylation of P38 mitogen‑activated protein kinase (MAPK) and p‑90 kDa ribosomal protein S6 kinase 1 proteins in CHMm cells. It was observed that paclitaxel in combination with pharmacological inhibitors of the P38 and phosphatidylinositol‑4,5‑bisphosphate 3‑kinase (PI3K) signaling pathways (SB203580 and LY294002, respectively) exerted synergistic inhibitory effects on the proliferation of the CHMm cells. The results of the present study demonstrated that paclitaxel inhibited tumor cell proliferation by increasing intrinsic apoptosis through inhibition of the PI3K/AKT signaling pathway and activation of MAPK signaling pathway in CHMm cells.

Paclitaxel suppresses proliferation and induces apoptosis through regulation of ROS and the AKT/MAPK signaling pathway in canine mammary gland tumor cells