Origanum majorana Essential Oil Triggers p38 MAPK-Mediated Protective Autophagy, Apoptosis, and Caspase-Dependent Cleavage of P70S6K in Colorectal Cancer Cells

Abstract

Colorectal cancer (CRC) is the third most common type of cancer in terms of incidence and mortality worldwide. Here we have investigated the anti-colon cancer potential of Origanum majorana essential oil (OMEO) and its underlying mechanisms of action. We showed that OMEO significantly inhibited the cellular viability and colony growth of human HT-29 colorectal cancer cells. OMEO induced protective autophagy, associated with downregulation of the mTOR/p70S6K pathway, and activated caspase-8 and caspase-9-dependent apoptosis. Blockade of autophagy with 3-methyladenine (3-MA) and chloroquine (CQ), two autophagy inhibitors, potentiated the OMEO-induced apoptotic cell death. Inversely, inhibition of apoptosis with the pan-caspase inhibitor, Z-VAD-FMK, significantly reduced cell death, suggesting that apoptosis represents the main mechanism of OMEO-induced cell death. Mechanistically, we found that OMEO induces protective autophagy and apoptotic cells death via the activation of the p38 MAPK signaling pathway. Pharmacological inhibition of p38 MAPK by the p38 inhibitors SB 202190 and SB 203580 not only significantly decreased apoptotic cell death, but also reduced the autophagy level in OMEO treated HT-29 cells. Strikingly, we found that OMEO also induces p38 MAPK-mediated caspase-dependent cleavage of p70S6K, a protein reported to be overexpressed in colon cancer and associated with drug resistance. Our findings suggest that OMEO inhibits colon cancer through p38 MAPK-mediated protective autophagy and apoptosis associated with caspase-dependent cleavage of p70S6K. To the best of our knowledge, this study is the first to report on the implications of the p38 MAPK signaling pathway in targeting p70S6K to caspase cleavage.

Memory-Enhancing Effects of Origanum majorana Essential Oil in an Alzheimer’s Amyloid beta1-42 Rat Model: A Molecular and Behavioral Study

“…The analysis of OmEO showed terpinen-4-ol (23.52%), sabinene (12.59%), terpinolene (8.72%), linalool (5.94%), β-thujene (4.60%), phellandrene (4.35%), and α-terpineol (4.30%) as the most abundant volatile components. Based on these findings, our essential oil exhibits a chemical composition equal to those documented by other authors [ 57 , 58 , 59 , 60 ].…”

Upregulation of CENPM facilitates tumor metastasis via the mTOR/p70S6K signaling pathway in pancreatic cancer

“…p70S6K has been revealed to be highly expressed and activated in several breast cancer cells ( 35 ). It has also been revealed to play crucial roles in tumor angiogenesis, cellular proliferation, migration and motility metastasis ( 36 – 38 ). Moreover, the mTOR/p70S6K signaling pathway was revealed to suppress autophagy through phosphorylation of transcription factor EB and restrain the expression of autophagy genes ( 39 , 40 ).…”

Bioactive Natural Compounds and Antioxidant Activity of Essential Oils from Spice Plants: New Findings and Potential Applications

“…The compounds from EO described with antioxidant activity represent a relevant fraction of their chemical composition [ 46 ]. These components have been indicated as an interesting source for the development and discovery of new bioactive compounds with pharmaceutical and cosmetic application due to their anti-inflammatory [ 47 ], antibacterial [ 48 ], antifungal [ 49 , 50 ], repellent [ 51 , 52 ], antioxidant [ 53 , 54 , 55 ], and neuroprotective [ 56 ] properties, as well as cytotoxic activities against cancer cell lines [ 57 , 58 ]. In addition, EOs and their constituents have been investigated as an alternative additive in the food industry [ 44 , 59 ] in contrast to synthetic antioxidants, such as butylated hydroxytoluene, butylated hydroxyanisole, and propyl gallate, that have exhibited undesired effects to human health [ 60 , 61 ].…”