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An Orthotopic Bladder Tumor Model and the Evaluation of Intravesical saRNA Treatment
Published on: July 28, 2012
Sulforaphane suppresses bladder cancer metastasis via blocking actin nucleation-mediated pseudopodia formation
Lei Huang1, Jiaxin Wang2, Xinyi Wang2
1School of Public Health, Wenzhou Medical University, Wenzhou, 325035, China; Department of Food Science and Nutrition, The Hong Kong Polytechnic University, 999077, Hong Kong Special Administrative Region.
Abstract:
Metastasis is the primary stumbling block to the treatment of bladder cancer (BC). In order to spread, tumor cells must acquire increased migratory and invasive capacity, which is tightly linked with pseudopodia formation. Here, we unravel the effects of sulforaphane (SFN), an isothiocyanate in cruciferous vegetables, on the assembly of pseudopodia and BC metastasis, and its molecular mechanism in the process. Our database analysis revealed that in bladder tumor, pseudopodia-associated genes, CTTN, WASL and ACTR2/ARP2 are upregulated. SFN caused lamellipodia to collapse in BC cells by blocking the CTTN-ARP2 axis. SFN inhibited invadopodia formation and cell invasion by reducing WASL in different invasive BC cell lines. The production of ATP, essential for the assembly of pseudopodia, was significantly increased in bladder tumors and strongly inhibited by SFN. Overexpressing AKT1 reversed the downregulation of ATP in SFN-treated bladder cancer cells and restored filopodia and lamellipodia morphology and function. Bioluminescent imaging showed that SFN suppressed BC metastases to the lung of nude mice while downregulating Cttn and Arp2 expression. Our study thus reveals mechanisms of SFN action in inhibiting pseudopodia formation and highlights potential targeting options for the therapy of metastatic bladder cancer.
Insights
Sulforaphane (SFN) inhibits bladder cancer (BC) metastasis by disrupting pseudopodia formation. SFN blocks key molecular pathways, reducing cell invasion and lung metastasis in mice.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Metastasis is a major challenge in bladder cancer (BC) treatment.
- Tumor cell migration and invasion, crucial for metastasis, depend on pseudopodia formation.
- Pseudopodia-associated genes like CTTN, WASL, and ACTR2/ARP2 are upregulated in bladder tumors.
Purpose of the Study:
- To investigate the effects of sulforaphane (SFN) on pseudopodia assembly and BC metastasis.
- To elucidate the molecular mechanisms underlying SFN's action in bladder cancer.
Main Methods:
- Database analysis of pseudopodia-associated genes.
- Cell culture experiments assessing lamellipodia and invadopodia formation.
- ATP production assays and AKT1 overexpression studies.
- In vivo bioluminescent imaging of lung metastasis in mice.
Main Results:
- SFN disrupts lamellipodia by blocking the CTTN-ARP2 axis in BC cells.
- SFN inhibits invadopodia formation and cell invasion by reducing WASL.
- SFN significantly inhibits ATP production, essential for pseudopodia assembly.
- Overexpression of AKT1 partially reverses SFN's effects on ATP and cell morphology.
- SFN suppressed lung metastasis in mice and downregulated Cttn and Arp2 expression.
Conclusions:
- SFN effectively inhibits bladder cancer cell pseudopodia formation and metastasis.
- SFN targets the CTTN-ARP2 axis and WASL to reduce cell invasion.
- SFN's inhibition of ATP production is a key mechanism in suppressing metastasis.
- SFN represents a potential therapeutic strategy for metastatic bladder cancer.
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