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Effect of selinexor on lipogenesis in virus-positive Merkel cell carcinoma cell lines
Jennifer R Landes1, Brooke R Bartley1, Stephen A Moore1
1Department of Dermatology, The University of Texas McGovern Medical School, Houston, TX, USA.
Background:
Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine cutaneous carcinoma aetiologically linked to the Merkel cell polyomavirus (MCPyV). Immune checkpoint inhibitors are currently the first-line therapy for metastatic MCC; however, the treatment is effective in only about half of patients, highlighting the need for alternative therapies. Selinexor (KPT-330) is a selective inhibitor of nuclear exportin 1 (XPO1) and has been shown to inhibit MCC cell growth in vitro, but the pathogenesis has not been established. Decades of research have established that cancer cells significantly upregulate lipogenesis to meet an increased demand for fatty acids and cholesterol. Treatments that inhibit lipogenic pathways may halt cancer cell proliferation.
Aim:
To determine the effect of increasing doses of selinexor on fatty acid and cholesterol synthesis in MCPyV-positive MCC (MCCP) cell lines and aid in elucidating the mechanism by which selinexor prevents and reduces MCC growth.
Methods:
MKL-1 and MS-1 cell lines were treated with increasing doses of selinexor for 72 h. Protein expression quantification was determined using chemiluminescent Western immunoblotting and densitometric analysis. Fatty acids and cholesterol were quantified using free fatty acid assay and cholesterol ester detection kits.
Results:
Selinexor causes statistically significant reductions of the lipogenic transcription factors sterol regulatory element-binding proteins 1 and 2, and lipogenic enzymes acetyl-CoA carboxylase, fatty acid synthase, squalene synthase and 3β-hydroxysterol Δ-24-reductase in a dose-dependent manner in two MCCP cell lines. Although inhibiting the fatty acid synthesis pathway results in meaningful decreases in fatty acids, the cellular cholesterol levels did not demonstrate such reductions.
Conclusion:
For patients with metastatic MCC refractory to immune checkpoint inhibitors, selinexor may provide clinical benefit through the inhibition of the lipogenesis pathway; however, further research and clinical trials are needed to evaluate these findings.
Insights
Selinexor significantly reduces fatty acid synthesis in Merkel cell carcinoma (MCC) by inhibiting key lipogenic factors. This finding suggests selinexor may offer a new treatment avenue for patients with advanced MCC resistant to current therapies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Merkel cell carcinoma (MCC) is an aggressive skin cancer linked to Merkel cell polyomavirus (MCPyV).
- Current treatments like immune checkpoint inhibitors are not effective for all patients, necessitating alternative therapies.
- Cancer cells often increase lipogenesis (fat and cholesterol synthesis) to support proliferation.
Purpose of the Study:
- To investigate the impact of selinexor on fatty acid and cholesterol synthesis in MCPyV-positive MCC (MCCP) cell lines.
- To elucidate the mechanism of selinexor's anti-cancer effects in MCC.
Main Methods:
- MKL-1 and MS-1 MCCP cell lines were treated with varying doses of selinexor for 72 hours.
- Protein expression of lipogenic factors was analyzed using Western immunoblotting.
- Quantification of fatty acids and cholesterol was performed using specific assay kits.
Main Results:
- Selinexor dose-dependently reduced key lipogenic transcription factors (SREBPs 1 and 2) and enzymes (ACC, FAS, SQS, DHCR24).
- Significant decreases in cellular fatty acid levels were observed.
- Cellular cholesterol levels did not show a comparable reduction.
Conclusions:
- Selinexor inhibits the lipogenesis pathway in MCCP cell lines, potentially by reducing fatty acid synthesis.
- This mechanism suggests selinexor could be a beneficial treatment for metastatic MCC refractory to immune checkpoint inhibitors.
- Further clinical trials are required to validate these preclinical findings.
