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

Ali H Eid,Khaled A El-Tarabily,Aysha Alneyadi,Asma Alrashedi,Abdulrasheed Palakott,Yusra Al Dhaheri,Rabah Iratni,Khawlah Athamneh,Halima Alsamri

doi:10.3390/biom10030412

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.

Highlights

Colorectal cancer (CRC) is the third most common type of cancer in terms of incidence and mortality, and affects both sexes almost [1]
To confirm the identity of the commercial Origanum majorana essential oil (OMEO) used in this study, the essential oil composition was analyzed by LC-MS and the identified compounds were compared with those reported in the literature
We have tested the effect of increasing concentrations at different times (6, 24, and 48 h) of OMEO on the proliferation of HT-29 colon cancer cells

Summary

Introduction

Colorectal cancer (CRC) is the third most common type of cancer in terms of incidence and mortality, and affects both sexes almost [1]. It has seen an increase in incidence in the past six decades and has become one of the predominant cancers (the third most common type); it accounts for approximately 10% of all cancer-related mortalities. Reasons that might explain the alarmingly increased incidence include an aging population (most patients diagnosed with CRC are age 50 and older), poor diet and lifestyle, smoking, a low rate of physical activity, and obesity [1]. CRC is a complex disease; it usually grows in the lining of the colon and the rectum in the form of a polyp, which is a mass bulging in the lumen. The majority of CRC evolves from adenomatous polyps [2]

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