Suppression of ERK1/2 and hypoxia pathways by four Phyllanthus species inhibits metastasis of human breast cancer cells

Abstract

Chemotherapies remain far from ideal due to drug resistance; therefore, novel chemotherapeutic agents with higher effectiveness are crucial. The extracts of four Phyllanthus species, namely Phyllanthus niruri, Phyllanthus urinaria, Phyllanthus watsonii, and Phyllanthus amarus, were shown to induce apoptosis and inhibit metastasis of breast carcinoma cells (MCF-7). The main objective of this study was to determine the pathways utilized by these four Phyllanthus species to exert anti-metastatic activities. A cancer 10-pathway reporter was used to investigate the pathways affected by the four Phyllanthus species. Results indicated that these Phyllanthus species suppressed breast carcinoma metastasis and proliferation by suppressing matrix metalloprotein 2 and 9 expression via inhibition of the extracellular signal-related kinase (ERK) pathway. Additionally, inhibition of hypoxia-inducible factor 1-α in the hypoxia pathway caused reduced vascular endothelial growth factor and inducible nitric oxide synthase expression, resulting in anti-angiogenic effects and eventually anti-metastasis. Two-dimensional gel electrophoresis identified numerous proteins suppressed by these Phyllanthus species, including invasion proteins, anti-apoptotic protein, protein-synthesis proteins, angiogenic and mobility proteins, and various glycolytic enzymes. Our results indicated that ERK and hypoxia pathways are the most likely targets of the four Phyllanthus species for the inhibition of MCF-7 metastasis.

The emerging role of xanthine oxidase inhibition for suppression of breast cancer cell migration and metastasis associated with hypercholesterolemia

“…ROS activate diverse signaling pathways, including the p42/p44 MAPK, p38 MAPK, and PI3K/Akt pathways (37) and have important roles, such as cell cycle, survival, and cell death. The MAPK and Wnt pathways are involved in the regulation of cancer cell proliferation, differentiation, and death (38,39). Here we evaluated the genes and signaling pathways that were altered in primary tumor tissues in a xenograft mouse model on an HCD with or without FBX cotreatment.…”

Cordycepin‐induced unfolded protein response‐dependent cell death, and AKT/MAPK‐mediated drug resistance in mouse testicular tumor cells

“…Studies have shown that MAPKs pathway is essential in the progression of cancer, which do control cell growth, migration, proliferation, and differentiation . MAPKs (ERK1/2, JNK and p38) are protein‐serine/threonine kinases, which could be activated through phosphorylation, beginning with the induction of MAPK kinase kinases (MAP3Ks) to adjust cell fates …”

“…MAPKs pathway is essential in cancer progression, which could control cell differentiation, proliferation, and migration . Studies have shown that the activation of MAPKs pathways is involved to the therapeutic resistance for various cancers .…”

“…MAPKs pathway is essential in cancer progression, which could control cell differentiation, proliferation, and migration. 34,35 Studies have shown that the activation of MAPKs pathways is involved to the therapeutic resistance for various cancers. 49,50 We have found that cordycepin did induce the expressions of phosphor-ERK and phosphor-JNK in attached F I G U R E 8 Cordycepin activating MAPK signaling pathways in attached and suspended MA-10 cells.…”

“…Studies have shown that MAPKs pathway is essential in the progression of cancer, which do control cell growth, migration, proliferation, and differentiation. 34,35 MAPKs (ERK1/2, JNK and p38) are protein-serine/threonine kinases, which could be activated through phosphorylation, beginning with the induction of MAPK kinase kinases (MAP3Ks) to adjust cell fates. 36 To investigate whether cordycepin could induce MAPK pathways for surviving related to drug resistance between attached and suspended MA-10 cells, the expressions of p-ERK, p-JNK, and p-P38 were analyzed by Western blotting after 24 hours of cordycepin treatments.…”