SERTAD1 Sensitizes Breast Cancer Cells to Doxorubicin and Promotes Lysosomal Protein Biosynthesis

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Acquired chemoresistance is a major obstacle in cancer therapy.
• Overcoming chemoresistance is crucial for improving patient outcomes.
• SERTAD1's role in cancer, particularly in chemoresistance, is not well understood.

Purpose of the Study:

• To investigate the role of SERTAD1 in chemoresistance and apoptosis/anoikis in breast cancer cells.
• To explore the potential of targeting SERTAD1 to enhance chemotherapy efficacy.

Main Methods:

• Analysis of SERTAD1 expression in different breast cancer cell lines under varying culture conditions.
• Treatment of cells with doxorubicin (Dox) at different doses to induce cell death.
• Inhibition of SERTAD1 and autophagy to assess combined effects on cell death and tumor growth.
• Evaluation of lysosomal content in SERTAD1-deficient cells.

Main Results:

• Higher SERTAD1 expression was observed in suspended MCF7 and MDA-MB-231 cells.
• Doxorubicin induced autophagy at low doses and apoptosis at high doses, potentially via lysosomal membrane permeabilization.
• SERTAD1 inhibition increased breast cancer cell sensitivity to doxorubicin and paclitaxel, reducing tumor volumes in vivo.
• Combined Dox and autophagy inhibition treatment led to increased apoptosis/anoikis.
• SERTAD1 deficiency resulted in reduced lysosomal contents (LAMP1, LAMP2, CTSB, CTSD).

Conclusions:

• SERTAD1 plays a suppressive role in apoptosis/anoikis, contributing to chemoresistance in breast cancer.
• Inhibiting SERTAD1 enhances sensitivity to chemotherapy drugs like doxorubicin and paclitaxel.
• Simultaneous targeting of SERTAD1, chemotherapy, and autophagy inhibition presents a potential therapeutic strategy to overcome chemoresistance and improve cancer treatment outcomes.