Triggering of p38 MAPK and JNK Signaling is Important for Oleanolic Acid‐Induced Apoptosis via the Mitochondrial Death Pathway in Hypertrophic Scar Fibroblasts

Abstract

Hypertrophic scarring is characterized by collagen overproduction and excessive deposition of extracellular matrix. No consensus arises currently about the best therapeutics to produce complete and permanent improvement of scars with few side effects. In the present study, the mechanism of oleanolic acid (OA)-induced apoptosis in hypertrophic scar fibroblasts (HSFs) was investigated for the first time. OA activated the protein phosphorylation of p38 MAPK and JNK but not ERK. OA did not antagonize the inhibitory effects of SB203580 on p38 MAPK pathway activity but sharply enhanced JNK phosphorylation when HSFs were pretreated with SB203580. Similarly, the inhibition of JNK signal pathway activation by pretreatment with SP600125 facilitated the protein phosphorylation of p38 MAPK caused by OA. Inhibition of p38 MAPK and/or JNK by inhibitors significantly enhanced cell viability and OA only partially depressed the increased cell viability. Moreover, OA increased Bax translocation, MMP loss, mitochondrial cytochrome c and AIF release, Bax and caspase-3 protein expression and the ratio of Bax to Bcl-2, decreased Bcl-2 protein expression, and elevated the mRNA expression of Apaf-1, caspase-9, and capase-3. These results suggest that OA elicits apoptosis through triggering of p38 MAPK and JNK signaling and activation of the mitochondrial death pathway. OA might be a good and useful natural drug against hypertrophic scars.

Transcriptomic and proteomic insight into the effects of a defined European mistletoe extract in Ewing sarcoma cells reveals cellular stress responses

“…Other ribosome-inactivating proteins as Ricin or Shiga toxins also activate MAPK8 and MAPK14 in human monocytes and macrophages [56–58]. Contrary to our results, the triterpenes oleanolic and betulinic acid were also shown to activate MAPK8 and MAPK14 in melanoma, pancreatic cancer and osteosarcoma cells and hypertrophic scar fibroblasts [19, 21, 59]. Since the activation of MAPK8 and MAPK14 is stress-mediated resulting in apoptosis and because our pathway analyses displayed response to oxidative stress and TLR signalling, we next investigated the impact of MAPK8, MAPK14 and TLR4 inhibitors and the anti-oxidant NAC on apoptosis induction in TC-71 cells upon treatment with the extracts.…”

Downregulation of Foxc2 enhances apoptosis induced by 5-fluorouracil through activation of MAPK and AKT pathways in colorectal cancer

“…The activation of several proteins, including ERK, JNK and AKT, is regulated by the MARK and PI3K/AKT pathways (30)(31)(32). The present study investigated whether PI3K and MAPKs are critical in the Foxc2 inhibition of apoptosis, and demonstrated that several MAPK-regulated proteins were upregulated in Foxc2-overexpressing CRC cells and downregulated in Foxc2-inhibited CRC cells.…”

Acetaminophen induces JNK/p38 signaling and activates the caspase-9-3-dependent cell death pathway in human mesenchymal stem cells

“…In the present study, whether APAP also activates the MAPK signaling pathways in hMSCs was examined. JNK, p38 and ERK belong to the MAPK family ( 59 , 60 ). Therefore, the phosphorylation levels of JNK, p38 and ERK were examined using western blot analysis in the present study.…”