Natural diterpenes from coffee, cafestol and kahweol induce apoptosis through regulation of specificity protein 1 expression in human malignant pleural mesothelioma

Abstract

BackgroundMalignant pleural mesothelioma (MPM) is a highly aggressive cancer with a very poor prognosis. Several clinical studies such as immunotherapy, gene therapy and molecular targeting agents have been tried for treatment of malignant mesothelioma, however, there is no application for effective clinical treatment. Coffee has various biological functions such as anti-oxidant, anti-inflammatory, anti-mutagenic and anti-carcinogenic activities. The therapeutic activities of the bioactive compounds in coffee was sugested to influence intracellular signaling of MPM. Regarding to the cancer-related functions, In this study, suppression of Sp1 protein level followed by induction of MSTO-211H cell apoptosis by cafestol and kahweol were investigated in oreder to determine Sp1's potential as a significant target for human MPM therapy as well.MethodsCells were treated separately with final concentration of cafestol and kahweol and the results were analyzed by MTS assay, DAPI staining, PI staining, luciferase assay, RT-PCR, and immunoblotting.ResultsViability of MSTO-211H and H28 cells were decreased, and apoptotic cell death was increased in MSTO-211H as a result of cafestol and kahweol treatment. Cafestol and kahweol increased Sub-G1 population and nuclear condensation in MSTO-211H cells. Roles of Sp1 in cell proliferation and apoptosis of the MSTO-211H cells by the Sp1 inhibitor of Mithramycin A were previously confirmed. Cafestol and kahweol significantly suppressed Sp1 protein levels. Kahweol slightly attenuated Sp1 mRNA, while Cafestol did not affect in MSTO-211H cells. Cafestol and kahweol modulated the promoter activity and protein expression level of the Sp1 regulatory genes including Cyclin D1, Mcl-1, and Survivin in mesothelioma cells. Apoptosis signaling cascade was activated by cleavages of Bid, Caspase-3, and PARP with cafestol and by upregulation of Bax, and downregulation of Bcl-xl by kahweol.ConclusionsSp1 can be a novel molecular target of cafestol and kahweol in human MPM.

Mithramycin A induces apoptosis by regulating the mTOR/Mcl-1/tBid pathway in androgen-independent prostate cancer cells

“…On the other hand, Mith can affect downstream targets such as Mcl-1 by displacing Sp1 transcription factor from its binding sites on the promoters of oncogenes to inhibit their expression. (16,31) Studies in this laboratory also previously demonstrated that Mith inhibits Mcl-1 protein to exhibit potent anti-tumorigenic activity in rodent models for prostate and oral cancers. (15,32) …”

Analytical methods applied for the characterization and the determination of bioactive compounds in coffee

“…These compounds and coffee drinking are positively correlated with higher level of serum cholesterol lipids, especially in patients with hyperlipidemia [81,82]. Latest research showed that they reduce the risk of colorectal cancer [83].…”

An insight towards anticancer potential of major coffee constituents

“…Wang et al also suggested an inhibitory effect by 5 mg of caffeine via cAMP/PKA/CREB signal suppression pathway through A 2A receptors treated for 8 weeks in male Sprague‐Dawley rats. Similarly, 30 µM of cafestol has also been noted to inhibit expression of Mcl‐1 and Sp1 protein (9 and 48 h of incubation, respectively) that affect the expression of cyclin D1 and survivin in mesothelioma cells .…”

“…In another study, Miglior et al [58] reported a reduction in apoptosis at 1 μM of caffeic acid in human umbilical vein endothelial cells. Similarly, cafestol has also been noted to cause apoptosis by cleavages of the Bid and caspase-3 in mesothelioma cells [38]. It has been also suggested to reduce apoptotic cell death and clonogenic survival in SCC25, CAL27, and FaDu cell lines [59].…”