Cannabidiol activates MAPK pathway to induce apoptosis, paraptosis, and autophagy in colorectal cancer cells

Mitogen‐activated protein kinase (MAPK) activation by natural compounds is known to be involved in the induction of apoptosis, paraptosis, and autophagy. Cannabidiol (CBD), a bioactive compound found in Cannabis sativa, is endowed with many pharmacological activities. We investigated the cytotoxic e...

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Published in:Journal of cellular biochemistry 2024-04, Vol.125 (4), p.e30537-n/a
Main Authors: Kim, Na Young, Mohan, Chakrabhavi Dhananjaya, Sethi, Gautam, Ahn, Kwang Seok
Format: Article
Language:English
Subjects:
Activating transcription factor 4
Apoptosis
Autophagy
Bioactive compounds
Biocompatibility
Cancer
Cannabidiol
Cannabidiol - pharmacology
Cannabinoids
Cannabis
Cell death
Cell Line, Tumor
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - drug therapy
Cytotoxicity
Endoplasmic reticulum
Flow cytometry
Humans
Kinases
MAP kinase
MAPKs
Mitogen-Activated Protein Kinases - metabolism
Oxygen
Paraptosis
Pharmacology
Proteins
Reactive oxygen species
Toxicity
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Summary:Mitogen‐activated protein kinase (MAPK) activation by natural compounds is known to be involved in the induction of apoptosis, paraptosis, and autophagy. Cannabidiol (CBD), a bioactive compound found in Cannabis sativa, is endowed with many pharmacological activities. We investigated the cytotoxic effect of CBD in a panel of colorectal cancer (CRC) cells (HT‐29, SW480, HCT‐116, and HCT‐15). CBD induced significant cytotoxicity as evidenced by the results of MTT  assay, live‐dead assay, and flow cytometric analysis. Since CBD displayed cytotoxicity against CRC cells, we examined the effect of CBD on apoptosis, paraptosis, and autophagy. CBD decreased the expression of antiapoptotic proteins and increased the Annexin‐V‐positive as well as TUNEL‐positive cells suggesting that CBD induces apoptosis. CBD increased the expression of ATF4 (activating transcription factor 4) and CHOP (CCAAT/enhancer‐binding protein homologous protein), elevated endoplasmic reticulum stress, and enhanced reactive oxygen species levels indicating that CBD also promotes paraptosis. CBD also induced the expression of Atg7, phospho‐Beclin‐1, and LC3 suggesting that CBD also accelerates autophagy. Since, the MAPK pathway is a common cascade that is involved in the regulation of apoptosis, paraptosis, and autophagy, we investigated the effect of CBD on the activation of JNK, p38, and ERK pathways. CBD activated all the forms of MAPK proteins and pharmacological inhibition of these proteins reverted the observed effects. Our findings implied that CBD could induce CRC cell death by activating apoptosis, paraptosis, and autophagy through the activation of the MAPK pathway.
ISSN:0730-2312
1097-4644
1097-4644
DOI:10.1002/jcb.30537