Inhibition of lysosomal TRPML1 channel eliminates breast cancer stem cells by triggering ferroptosis

Area of Science:

• Oncology
• Cell Biology
• Molecular Medicine

Background:

• Cancer stem cells (CSCs) drive therapeutic resistance, metastasis, and recurrence in breast cancer.
• Effective CSC eradication is critical for improving patient outcomes but remains challenging.
• TRPML1, a lysosomal cation channel, is implicated in cellular processes relevant to cancer.

Purpose of the Study:

• To investigate TRPML1 as a potential therapeutic target for eliminating breast cancer stem cells (CSCs).
• To evaluate the effects of TRPML1 inhibition on CSC stemness, ferroptosis, and chemosensitivity.
• To assess the in vivo efficacy of targeting TRPML1 in a breast cancer xenograft model.

Main Methods:

• Analysis of TRPML1 expression in breast cancer cells.
• Pharmacological inhibition and genetic depletion of TRPML1.
• Assessment of ferroptosis induction and stemness reduction in CSCs.
• Evaluation of chemosensitivity to doxorubicin.
• In vivo studies using a mouse xenograft model to assess tumor suppression.

Main Results:

• TRPML1 is highly expressed in breast cancer cells and sensitive to salinomycin, a CSC-eliminating drug.
• TRPML1 inhibition or knockout promotes ferroptosis and reduces stemness in breast CSCs.
• Targeting TRPML1 enhances breast cancer cell sensitivity to doxorubicin.
• TRPML1 inhibition significantly suppresses tumor formation and growth in vivo.

Conclusions:

• TRPML1 is a promising therapeutic target for eradicating breast cancer stem cells.
• TRPML1-targeted strategies may overcome therapeutic resistance and improve treatment efficacy.
• Eliminating CSCs by targeting TRPML1 offers a novel approach for breast cancer treatment.