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Adenosine Inhibits Cholangiocarcinoma by a Concurrent Activation of AMPK and mTORC1 Signaling Pathways
Jomnarong Lertsuwan1, Jisnuson Svasti2, Jutamaad Satayavivad3
1Laboratory of Immunology, Chulabhorn Research Institute, Bangkok, Thailand; jomnarong@cri.or.th.
Background/Aim:
Cholangiocarcinoma (CCA) is a highly aggressive cancer for which current chemotherapies offer limited effectiveness. However, recent research suggests a promising new approach using adenosine. Studies have shown that adenosine can inhibit CCA cell growth while having minimal harmful effects on immortalized cholangiocytes (imCho). This particular study delved deeper into these findings, investigating the specific effects of adenosine on CCA and imCho to better understand its therapeutic potential against this disease.
Materials And Methods:
Cell growth was examined using the MTT assay. Cell invasion was examined using the transwell assay. Cell death was evaluated using flow cytometry. Protein levels were examined using western blot analysis. Animal experiment was performed in Balb/cAJcl-Nu mice.
Results:
Adenosine demonstrated differential effects on CCA cells compared to imCho. Specifically, adenosine induced endoplasmic reticulum (ER) stress in CCA cells but not in imCho. When combined with hydroxychloroquine (an autophagy inhibitor), apoptosis was greatly enhanced in CCA cells. This combination exhibited a more pronounced deleterious effect on CCA cells than on imCho cells, suggesting a potential for selective targeting. While adenosine alone demonstrated the ability to slow CCA growth in vitro, it did not induce apoptosis in this setting. However, in vivo tumor xenograft studies revealed comparable tumor sizes between adenosine monotherapy and the adenosine-hydroxychloroquine combination. Notably, the combination group exhibited a higher number of apoptotic cells. Further investigation into the molecular mechanisms revealed that adenosine activated both AMPK and mTORC1 signaling pathways. Crucially, the mTORC1 pathway was found to be essential for adenosine's ability to inhibit CCA cell growth and invasion.
Conclusion:
A co-activation of AMPK and mTORC1 signaling pathways in CCA cells after adenosine treatment. Both pathways are necessary for adenosine to inhibit CCA cell growth and invasion.
Insights
Adenosine shows promise in treating cholangiocarcinoma (CCA) by inhibiting cancer cell growth and invasion. Combining adenosine with hydroxychloroquine enhances its effectiveness, targeting CCA cells selectively.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Cholangiocarcinoma (CCA) is an aggressive cancer with limited treatment options.
- Adenosine has shown potential in inhibiting CCA cell growth with minimal toxicity to normal cells.
- Understanding adenosine's specific effects on CCA is crucial for developing new therapies.
Purpose of the Study:
- To investigate the differential effects of adenosine on CCA cells and immortalized cholangiocytes (imCho).
- To explore the molecular mechanisms underlying adenosine's anti-cancer activity in CCA.
- To evaluate the therapeutic potential of adenosine, alone and in combination with hydroxychloroquine, against CCA.
Main Methods:
- Cell growth was assessed using MTT assays.
- Cell invasion was analyzed via transwell assays.
- Apoptosis and protein levels were evaluated using flow cytometry and western blot analysis, respectively.
- In vivo studies were conducted in Balb/cAJcl-Nu mice.
Main Results:
- Adenosine induced endoplasmic reticulum (ER) stress selectively in CCA cells, not imCho.
- Combining adenosine with hydroxychloroquine enhanced apoptosis in CCA cells more than in imCho.
- Adenosine activated both AMPK and mTORC1 signaling pathways, with mTORC1 being essential for inhibiting CCA cell growth and invasion.
- In vivo studies showed comparable tumor sizes but increased apoptosis with the adenosine-hydroxychloroquine combination.
Conclusions:
- Adenosine treatment leads to co-activation of AMPK and mTORC1 signaling pathways in CCA cells.
- Both AMPK and mTORC1 pathways are critical for adenosine's inhibitory effects on CCA cell growth and invasion.
- The combination of adenosine and hydroxychloroquine demonstrates selective targeting and enhanced therapeutic potential against CCA.
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