Cantharidin Induced Oral Squamous Cell Carcinoma Cell Apoptosis via the JNK-Regulated Mitochondria and Endoplasmic
Chin-Chuan Su1,2, Kuan-I Lee3, Mu-Kuan Chen2
1Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.
Abstract:
Oral cancer is a subtype of head and neck cancer which represents 2.65% of all human malignancies. Most of oral cancer is histopathologically diagnosed as oral squamous cell carcinoma (OSCC). OSCC is characterized by a high degree of local invasion and a high rate of metastasis to the cervical lymph nodes. How to prevention and treatment of OSCC is important and imperative. Here, we investigated the therapeutic effect and molecular mechanism of cantharidin, an active compound isolated from blister beetles, on OSCC in vitro. Results showed that cantharidin significantly decreased cell viability in human tongue squamous carcinoma-derived SAS, CAL-27, and SCC-4 cell lines. The further mechanistic studies were carried out in SAS cells. Cantharidin also significantly increased apoptosis-related signals, including caspase-9, caspase-7 and caspase-3 proteins. Besides, cantharidin decreased mitochondrial transmembrane potential (MMP) and induced cytochrome c and apoptosis inducing factor (AIF) release. Cantharidin also increased Bax, Bid, and Bak protein expressions and decreased Bcl-2 protein expression. Cantharidin could also increase the endoplasmic reticulum (ER) stress signals, including the expressions of phosphorylated eIF-2α and CHOP, but not Grp78 and Grp94. Furthermore, cantharidin reduced pro-caspase-12 protein expression. In signals of mitogen-activated protein kinases, cantharidin increased the phosphorylation of JNK, but not ERK and p38. Transfection of shRNA-JNK to OSCC cells effectively reversed the cantharidin-induced cell apoptotic signals, including the mitochondrial and ER stress-related signaling molecules. Taken together, these findings suggest that cantharidin induces apoptosis in OSCC cells via the JNK-regulated mitochondria and ER stress-related signaling pathways.
Insights
Cantharidin, a compound from blister beetles, effectively reduces oral squamous cell carcinoma (OSCC) viability by inducing apoptosis through JNK-regulated mitochondrial and ER stress pathways. This research offers insights into potential new treatments for oral cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Oral squamous cell carcinoma (OSCC) is a significant subset of head and neck cancers, known for aggressive local invasion and metastasis.
- Effective prevention and treatment strategies for OSCC remain a critical unmet need in clinical oncology.
- Cantharidin, a compound derived from blister beetles, has shown potential as a therapeutic agent.
Purpose of the Study:
- To investigate the therapeutic effects of cantharidin on OSCC cell lines in vitro.
- To elucidate the molecular mechanisms underlying cantharidin's action in OSCC cells.
Main Methods:
- Assessed cantharidin's effect on cell viability in human OSCC cell lines (SAS, CAL-27, SCC-4).
- Analyzed apoptosis-related signaling pathways, including caspases, mitochondrial membrane potential, and Bcl-2 family proteins.
- Investigated endoplasmic reticulum (ER) stress markers and mitogen-activated protein kinase (MAPK) pathways, specifically JNK.
Main Results:
- Cantharidin significantly reduced OSCC cell viability and induced apoptosis.
- Mechanistically, cantharidin triggered caspase activation, decreased mitochondrial membrane potential, and modulated Bcl-2 family proteins.
- Cantharidin induced ER stress and activated the JNK pathway, which was found to be crucial for mediating apoptosis.
Conclusions:
- Cantharidin demonstrates significant anti-cancer effects against OSCC cells in vitro.
- The JNK signaling pathway plays a pivotal role in mediating cantharidin-induced apoptosis via mitochondrial and ER stress pathways.
- Cantharidin represents a promising therapeutic candidate for OSCC, warranting further investigation.
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