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Published on: July 17, 2020
Targeting PELP1 oncogenic signaling in TNBC with the small molecule inhibitor SMIP34
Kristin A Altwegg1,2, Uday P Pratap1, Zexuan Liu1,3
1Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
Purpose:
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Oncogenic PELP1 is frequently overexpressed in TNBC, and it has been demonstrated that PELP1 signaling is essential for TNBC progression. The therapeutic utility of targeting PELP1 in TNBC, however, remains unknown. In this study, we investigated the effectiveness of SMIP34, a recently developed PELP1 inhibitor for the treatment of TNBC.
Methods:
To ascertain the impact of SMIP34 treatment, we used seven different TNBC models for testing cell viability, colony formation, invasion, apoptosis, and cell cycle analysis. Western blotting and RT-qPCR were used to determine the mechanistic insights of SMIP34 action. Using xenograft and PDX tumors, the ability of SMIP34 in suppressing proliferation was examined both ex vivo and in vivo.
Results:
TNBC cells' viability, colony formation, and invasiveness were all decreased by SMIP34 in in vitro cell-based assays, while apoptosis was increased. SMIP34 treatment promoted the degradation of PELP1 through the proteasome pathway. RT-qPCR analyses confirmed that SMIP34 treatment downregulated PELP1 target genes. Further, SMIP34 treatment substantially downregulated PELP1 mediated extranuclear signaling including ERK, mTOR, S6 and 4EBP1. Mechanistic studies confirmed downregulation of PELP1 mediated ribosomal biogenesis functions including downregulation of cMyc and Rix complex proteins LAS1L, TEX-10, and SENP3. The proliferation of TNBC tumor tissues was decreased in explant experiments by SMIP34. Additionally, SMIP34 treatment markedly decreased tumor progression in both TNBC xenograft and PDX models.
Conclusions:
Together, these findings from in vitro, ex vivo, and in vivo models show that SMIP34 may be a useful therapeutic agent for inhibiting PELP1 signaling in TNBC.
Insights
The PELP1 inhibitor SMIP34 effectively suppressed triple-negative breast cancer (TNBC) progression in preclinical models. SMIP34 demonstrated therapeutic potential by reducing tumor viability, invasion, and proliferation while increasing apoptosis in TNBC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with limited targeted therapies.
- PELP1 signaling is crucial for TNBC progression, but its therapeutic targeting remains unexplored.
- PELP1 overexpression is a hallmark of TNBC, driving its aggressive nature.
Purpose of the Study:
- To investigate the therapeutic efficacy of SMIP34, a novel PELP1 inhibitor, against TNBC.
- To evaluate SMIP34's impact on TNBC cell viability, proliferation, invasion, and apoptosis.
- To elucidate the molecular mechanisms underlying SMIP34's action in TNBC models.
Main Methods:
- Utilized seven TNBC cell line models for in vitro assays (viability, colony formation, invasion, apoptosis, cell cycle).
- Employed Western blotting and RT-qPCR to analyze molecular changes and signaling pathways.
- Assessed SMIP34's anti-proliferative effects ex vivo and in vivo using xenograft and patient-derived tumor (PDX) models.
Main Results:
- SMIP34 significantly reduced TNBC cell viability, colony formation, and invasiveness while enhancing apoptosis in vitro.
- Treatment with SMIP34 led to PELP1 degradation via the proteasome pathway and downregulated PELP1 target genes.
- SMIP34 inhibited PELP1-mediated signaling (ERK, mTOR, S6, 4EBP1) and ribosomal biogenesis, suppressing tumor growth in vivo.
Conclusions:
- SMIP34 demonstrates potent anti-cancer activity against TNBC across in vitro, ex vivo, and in vivo models.
- The findings suggest SMIP34 is a promising therapeutic candidate for targeting PELP1 signaling in TNBC.
- SMIP34 effectively inhibits key oncogenic pathways essential for TNBC progression.
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