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Potential anticancer effect of prostratin through SIK3 inhibition
Dalal Alotaibi1, Suneetha Amara2, Terrance L Johnson1
1Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, USA.
Abstract:
Prostratin, a phorbol ester natural plant compound, has been demonstrated to exert an anti-retroviral effect through activation of latent cluster of differentiation (CD)4+T lymphocytes and inhibition of viral entry into the cell through downregulation of chemokine receptor type 4 (CXCR4) expression. However, the potential effect of prostratin on cancer is yet to be defined. As CXCR4 is well known to induce cancer migration, it was hypothesized that prostratin induces an anti-cancer effect through inhibition of CXCR4 expression. The authors previously demonstrated that high stimulating conditions (sub-minimal IL-17, 0.1 ng/ml, synergized with high salt, Δ0.05 M NaCl) promote breast cancer cell proliferation and CXCR4 expression through upregulation of salt-inducible kinase (SIK)-3. The present study demonstrated that prostratin selectively exerted increased cytotoxicity (IC50 of 7 µM) when breast cancer cells were cultured in high stimulating conditions, compared with regular basal culture conditions (IC50 of 35 µM). Furthermore, the cytotoxic potential of prostratin was increased seven-fold in the four breast cancer cell lines (MCF-7, MDA-MB-231, BT-20 and AU-565) compared with the non-malignant MCF10A breast epithelial cell line. This suggested that prostratin specifically targets cancer cells over normal cells. Mechanistic studies revealed that prostratin inhibited CXCR4 expression in breast cancer cells through downregulation of SIK3 expression. Overall, the data suggest that prostratin is a novel drug target for the pro-oncogenic factor SIK3. These studies could form a basis for further research to evaluate the anticancer effect of prostratin in a combinatorial chemotherapeutic regimen.
Insights
Prostratin shows anti-cancer effects by reducing breast cancer cell growth and targeting the SIK3 protein. This natural compound is more effective against cancer cells than normal cells, suggesting its potential in cancer therapy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Prostratin, a natural compound, has known anti-retroviral properties via CD4+ T lymphocyte activation and CXCR4 downregulation.
- CXCR4 is implicated in cancer migration, suggesting a potential anti-cancer role for prostratin.
- Previous work linked high salt and IL-17 conditions to breast cancer proliferation and CXCR4/SIK3 upregulation.
Purpose of the Study:
- To investigate the anti-cancer effects of prostratin, specifically its impact on breast cancer cells.
- To determine if prostratin inhibits cancer cell migration by targeting CXCR4 expression.
- To explore the relationship between prostratin, SIK3, and breast cancer cell proliferation.
Main Methods:
- Assessing prostratin's cytotoxicity (IC50) in breast cancer cell lines under basal and high-stimulating conditions.
- Comparing prostratin's effect on malignant versus non-malignant breast cells.
- Investigating the molecular mechanisms, including CXCR4 and SIK3 expression levels, affected by prostratin treatment.
Main Results:
- Prostratin exhibited significantly higher cytotoxicity in breast cancer cells under high-stimulating conditions (IC50 = 7 µM) compared to basal conditions (IC50 = 35 µM).
- Prostratin demonstrated a seven-fold greater cytotoxic effect on breast cancer cell lines (MCF-7, MDA-MB-231, BT-20, AU-565) relative to the non-malignant MCF10A cell line.
- Mechanistic studies showed prostratin inhibits CXCR4 expression by downregulating SIK3 expression in breast cancer cells.
Conclusions:
- Prostratin selectively targets breast cancer cells, showing increased efficacy under specific stimulating conditions.
- Prostratin's anti-cancer mechanism involves the downregulation of SIK3, a pro-oncogenic factor, leading to reduced CXCR4 expression.
- Prostratin represents a potential therapeutic agent and a novel drug target for SIK3 in cancer treatment, warranting further investigation in combination therapies.
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