Mertensene, a Halogenated Monoterpene, Induces G2/M Cell Cycle Arrest and Caspase Dependent Apoptosis of Human Colon Adenocarcinoma HT29 Cell Line through the Modulation of ERK-1/-2, AKT and NF-κB Signaling

Abstract

Conventional treatment of advanced colorectal cancer is associated with tumor resistance and toxicity towards normal tissues. Therefore, development of effective anticancer therapeutic alternatives is still urgently required. Nowadays, marine secondary metabolites have been extensively investigated due to the fact that they frequently exhibit anti-tumor properties. However, little attention has been given to terpenoids isolated from seaweeds. In this study, we isolated the halogenated monoterpene mertensene from the red alga Pterocladiella capillacea (S.G. Gmelin) Santelices and Hommersand and we highlight its inhibitory effect on the viability of two human colorectal adenocarcinoma cell lines HT29 and LS174. Interestingly, exposure of HT29 cells to different concentrations of mertensene correlated with the activation of MAPK ERK-1/-2, Akt and NF-κB pathways. Moreover, mertensene-induced G2/M cell cycle arrest was associated with a decrease in the phosphorylated forms of the anti-tumor transcription factor p53, retinoblastoma protein (Rb), cdc2 and chkp2. Indeed, a reduction of the cellular level of cyclin-dependent kinases CDK2 and CDK4 was observed in mertensene-treated cells. We also demonstrated that mertensene triggers a caspase-dependent apoptosis in HT29 cancer cells characterized by the activation of caspase-3 and the cleavage of poly (ADP-ribose) polymerase (PARP). Besides, the level of death receptor-associated protein TRADD increased significantly in a concentration-dependent manner. Taken together, these results demonstrate the potential of mertensene as a drug candidate for the treatment of colon cancer.

Anticancer Activities of Meroterpenoids Isolated from the Brown Alga Cystoseira usneoides against the Human Colon Cancer Cells HT-29

“…In this study, we demonstrated that the growth inhibitory effect of the AMTs 1, 2, 3, 4, 5, and 7 on HT-29 cancer cells is associated with a G2/M arrest and cell cycle progression. These results are in line with an earlier report that demonstrated that the algal halogenated monoterpene mertensene induced similar response with G2/M arrest from HT-29 cells [33]. However, other algal terpenes have been described to induce cell cycle arrest in G1 phase in different types of cell lines [36,37].…”

“…In the present study, we found that the AMTs 1, 2, 3, 4, 7, and 8 reduce the protein levels of p-AKT in HT-29 cells, indicating the role of these AMTs in the downregulation of proliferation, cell cycle, apoptosis, and metastasis in colon cancer cells through the regulation of MAPK and AKT pathways. These results are in line with a previous study where the algal halogenated monoterpene mertensene was shown to induce G2/M cell cycle arrest and apoptosis in human colon adenocarcinoma HT-29, through the modulation of ERK-1/-2 and AKT signaling [33]. Nonetheless, some studies on the mechanism of action of other algal terpenoids have also demonstrated the intervention of other signaling pathways.…”

“…In particular, the AMT tuberatolide B, isolated from the alga Sargassum macrocarpum [31], has been shown to inhibit the viability of various cancer cell lines, including breast cancer (MDA-MB-231), lung cancer (A549), and colon cancer (HCT116), by inducing apoptotic cell death, and sargachromanol E, from Sargassum siliquastrum, has been reported to induce apoptosis in the colon cancer cell line HL-60 [32]. On the other hand, in the last years a variety of algal terpenoids have been reported to induce apoptosis in several cancer cells, including HT-29 [33], Jurkat leukemic cells [34], melanoma B16F10 cells [35,36], and human TNBC cells [37].…”

Structural and functional characterization of β2‐glycoprotein I domain 1 in anti‐melanoma cell migration

“…Here, we also elucidated the possible β 2 ‐GPI‐mediated molecular mechanisms by western blot analysis. Alterations of AKT, ERK1/2, p38, and NF‐κB activation are known in tumorigenesis . We thus expect that β 2 ‐GPI and D1 polypeptide may regulate these signaling pathways and consequently inhibit melanoma cell migration, cell proliferation, and tumor growth.…”

“…Alterations of AKT, ERK1/2, p38, and NF-κB activation are known in tumorigenesis. [31][32][33][34] We thus expect that β 2 -GPI and D1 polypeptide may regulate these signaling pathways and consequently inhibit melanoma cell migration, cell proliferation, and tumor growth.…”