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

被引:48
|
作者
Athamneh, Khawlah [1 ]
Alneyadi, Aysha [1 ]
Alsamri, Halima [1 ]
Alrashedi, Asma [1 ]
Palakott, Abdulrasheed [1 ]
El-Tarabily, Khaled A. [1 ,2 ]
Eid, Ali H. [3 ]
Al Dhaheri, Yusra [1 ]
Iratni, Rabah [1 ]
机构
[1] United Arab Emirates Univ, Coll Sci, Dept Biol, POB 15551, Al Ain, U Arab Emirates
[2] United Arab Emirates Univ, Khalifa Ctr Genet Engn & Biotechnol, POB 15551, Al Ain, U Arab Emirates
[3] Amer Univ Beirut, Fac Med, Dept Pharmacol & Toxicol, Beirut 11072020, Lebanon
关键词
Origanum majorana; colon cancer; autophagy; apoptosis; p38MAPK; p70S6K; ANTIMICROBIAL ACTIVITY; MAMMALIAN TARGET; L; KINASE; TUMORIGENESIS; SUPPRESSION; INHIBITION; RESISTANCE; LIFE;
D O I
10.3390/biom10030412
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:18
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