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A 5' AMP-Activated Protein Kinase Enzyme Activator, Compound 59, Induces Autophagy and Apoptosis in Human Oral
Jing-Ru Weng1, Eman M E Dokla2, Li-Yuan Bai3,4
1Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan.
Abstract:
5' AMP-activated protein kinase enzyme (AMPK), a master regulator of cellular metabolism, is recognized for its association with various metabolic diseases, inflammation and cancer. In this study, we aimed to investigate the role of compound 59, an AMPK activator, in a panel of oral squamous cell carcinoma (OSCC) cell lines. The antiproliferative effects of compound 59 were assessed by MTT assays, flow cytometry, Western blotting, confocal microscopy and transmission electron microscopy. Relative to OSCC cells, normal human oral keratinocytes were almost insensitive to compound 59 treatment. Compound 59 induced apoptosis as indicated by caspase activation and PARP cleavage. In addition, it inhibited JAK/STAT3 signalling, arrested cells in the G1 phase, increased reactive oxygen species (ROS) generation and promoted autophagy. Interestingly, pre-treatment with a protein tyrosine phosphatase (PP2A) inhibitor, cantharidin, partially reversed compound 59-induced down-regulation of p-JAK2 and p-STAT3, thereby suggesting the involvement of a protein tyrosine phosphatase. Together, these findings substantiate the potential of compound 59 for the treatment of OSCC patients.
Insights
Compound 59, an activator of 5' AMP-activated protein kinase enzyme (AMPK), shows significant antiproliferative effects against oral squamous cell carcinoma (OSCC) by inducing apoptosis and inhibiting key signaling pathways. This suggests its potential as an OSCC therapeutic agent.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- 5' AMP-activated protein kinase enzyme (AMPK) is a crucial regulator of cellular metabolism, implicated in metabolic diseases, inflammation, and cancer.
- Oral squamous cell carcinoma (OSCC) is a prevalent malignancy requiring novel therapeutic strategies.
Purpose of the Study:
- To investigate the therapeutic potential of compound 59, an AMPK activator, in oral squamous cell carcinoma (OSCC) cell lines.
- To elucidate the molecular mechanisms underlying the effects of compound 59 in OSCC.
Main Methods:
- MTT assays, flow cytometry, Western blotting, confocal microscopy, and transmission electron microscopy were employed.
- Cellular apoptosis, cell cycle progression, reactive oxygen species (ROS) generation, and autophagy were analyzed.
- The involvement of JAK/STAT3 signaling and protein tyrosine phosphatase (PP2A) was assessed.
Main Results:
- Compound 59 exhibited significant antiproliferative effects on OSCC cells, with minimal impact on normal oral keratinocytes.
- Compound 59 induced apoptosis, G1 phase arrest, increased ROS production, and promoted autophagy in OSCC cells.
- Inhibition of JAK/STAT3 signaling was observed, with partial reversal by a PP2A inhibitor, suggesting phosphatase involvement.
Conclusions:
- Compound 59 demonstrates potent anti-OSCC activity through multiple mechanisms, including apoptosis induction and signaling pathway modulation.
- The findings support the potential of compound 59 as a novel therapeutic agent for oral squamous cell carcinoma patients.