Methylseleninic Acid Suppresses Breast Cancer Growth via the JAK2/STAT3 Pathway

Abstract

Previous studies show that methylseleninic acid (MSA), which is the most common selenium derivative used as a drug in humans, exerts specific cytotoxic effects in several cancer cell types. However, the complex mechanism of these effects has not been fully elucidated. Here, we demonstrate by Cell Counting Kit-8 in mouse breast cancer cell line 4T1 that MSA inhibits cell viability in a concentration-dependent (5, 10, 20 μmol/L) and time-dependent (6, 12, 24 hours) manner. Flow cytometry, Western blot, and Reverse Transcription-Polymerase Chain Reaction (RT-PCR) analyses indicated that MSA inhibits cancer cell invasion and induces apoptosis by the activation of caspase-3, poly ADP ribose polymerase 1 (PARP1), and BCL2-associated X. Furthermore, MSA demonstrated anticancer activity by inhibiting the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) pathway. The MSA treatment for 24 hours decreased the phosphorylation of JAK2 and STAT3 in 4T1 cells by Western blot. We also confirmed this with the use of a JAK2 chemical inhibitor, AG490, as a positive control. In a 4T1 orthotopic allograft model, morphological and TdT-mediated dUTP nick-end labeling analyses showed that MSA treatment (1.5 mg/kg/weight) for 28 days inhibits tumor growth consistent with the clinical anticancer drug cyclophosphamide. Our observations demonstrate that MSA is a potent anticancer drug in breast cancer and uncovered a key role of the JAK2/STAT3 pathway in modulating tumor growth.

Role of STAT3 signaling pathway in breast cancer

“…Other compounds target different signaling pathways, including the JAK2/STAT3 and Akt pathways. Both ganoderic acid A, which is isolated from ganoderma, and methylseleninic acid are found to suppress breast cancer proliferation via the JAK2/STAT3 pathway [82,83]. A compound called caffeic acid p-nitro-phenethyl ester (CAPE-pNO 2 ) is found to inhibit the EGFR/STAT3/Akt pathway and suppress breast cancer proliferation and metastasis [88].…”

Quercetin shows anti‐tumor effect in hepatocellular carcinoma LM3 cells by abrogating JAK2/STAT3 signaling pathway

“…8,[16][17][18] As a cytokine, the transcription factor STAT3, has been testified that it is closely associated with tumor development. STAT3 can inhibit apoptosis and autophagy, [19][20][21] and promote migration/ invasion 16,22,23 of primary cancers, such as liver cancer. After activation, STAT3 will translocate into the nucleus and regulate transcription.…”

The Main Cytotoxic Effects of Methylseleninic Acid on Various Cancer Cells

“…Using 4T1 mouse malignant breast cancer cells as an example, it was shown that MSA significantly induced apoptosis of these cancer cells by activating Bax, caspase-3, PARP [59]. In addition, MSA was able to inhibit tumor angiogenesis by reducing the expression of vascular endothelial growth factors VEGF and Ang-2 in mammary cells of dogs and mouse models.…”

“…[ 59,60] WM1552c, UKRV, Colo875 (human melanoma cell lines), SK-BR-3, BT-474 (human mammary carcinoma cell lines), B16F10 (mouse skin melanoma cells)…”