SRT1720 induces lysosomal-dependent cell death of breast cancer cells
Tyler J Lahusen1, Chu-Xia Deng1
1Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, NIH, Bethesda, Maryland. cxdeng@umac.mo tylerlah@gmail.com.
Abstract:
SRT1720 is an activator of SIRT1, a NAD(+)-dependent protein and histone deacetylase that plays an important role in numerous biologic processes. Several studies have illustrated that SRT1720 treatment could improve metabolic conditions in mouse models and in a study in cancer SRT1720 caused increased apoptosis of myeloma cells. However, the effect of SRT1720 on cancer may be complex, as some recent studies have demonstrated that SRT1720 may not directly activate SIRT1 and another study showed that SRT1720 treatment could promote lung metastasis. To further investigate the role of SRT1720 in breast cancer, we treated SIRT1 knockdown and control breast cancer cell lines with SRT1720 both in vitro and in vivo. We showed that SRT1720 more effectively decreased the viability of basal-type MDA-MB-231 and BT20 cells as compared with luminal-type MCF-7 breast cancer cells or nontumorigenic MCF-10A cells. We demonstrated that SRT1720 induced lysosomal membrane permeabilization and necrosis, which could be blocked by lysosomal inhibitors. In contrast, SRT1720-induced cell death occurred in vitro irrespective of SIRT1 status, whereas in nude mice, SRT1720 exhibited a more profound effect in inhibiting the growth of allograft tumors of SIRT1 proficient cells as compared with tumors of SIRT1-deficient cells. Thus, SRT1720 causes lysosomal-dependent necrosis and may be used as a therapeutic agent for breast cancer treatment.
Insights
SRT1720 induces breast cancer cell death through lysosome-dependent necrosis, independent of SIRT1 status in vitro. This compound shows therapeutic potential for breast cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- SRT1720 is a SIRT1 activator with complex effects in cancer.
- Previous studies show mixed results regarding SRT1720's impact on cancer cell apoptosis and metastasis.
- The precise mechanism and SIRT1 dependency of SRT1720 in breast cancer remain unclear.
Purpose of the Study:
- To investigate the role and mechanism of SRT1720 in breast cancer.
- To determine the effect of SRT1720 on different breast cancer subtypes.
- To evaluate the influence of SIRT1 status on SRT1720's efficacy.
Main Methods:
- Treatment of breast cancer cell lines (MDA-MB-231, BT20, MCF-7) and non-tumorigenic cells (MCF-10A) with SRT1720 in vitro.
- Assessment of cell viability and induction of cell death pathways.
- In vivo studies using nude mice with SIRT1 knockdown and control tumors.
- Investigation of lysosomal membrane permeabilization and necrosis.
Main Results:
- SRT1720 decreased viability in basal-type breast cancer cells more effectively than luminal-type cells.
- SRT1720 induced lysosomal membrane permeabilization and necrosis, which were blocked by lysosomal inhibitors.
- In vitro, SRT1720-induced cell death was independent of SIRT1 status.
- In vivo, SRT1720 showed a more profound tumor growth inhibition in SIRT1-proficient tumors compared to SIRT1-deficient tumors.
Conclusions:
- SRT1720 induces breast cancer cell death via lysosomal-dependent necrosis.
- SRT1720's efficacy in vivo may be influenced by SIRT1 status.
- SRT1720 demonstrates potential as a therapeutic agent for breast cancer.
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