2. Academic Validation
  3. Targeting PELP1 oncogenic signaling in TNBC with the small molecule inhibitor SMIP34

Targeting PELP1 oncogenic signaling in TNBC with the small molecule inhibitor SMIP34

  • Breast Cancer Res Treat. 2023 Jul;200(1):151-162. doi: 10.1007/s10549-023-06958-4.
Kristin A Altwegg 1 2,  Uday P Pratap 1,  Zexuan Liu 1 3,  Junhao Liu 1 3,  John R Sanchez 1,  Xue Yang 1 4,  Behnam Ebrahimi 1 2,  Durga Meenakshi Panneerdoss 1,  Xiaonan Li 1,  Gangadhara R Sareddy 1 2,  Suryavathi Viswanadhapalli 1 2,  Manjeet K Rao 5 2,  Ratna K Vadlamudi 6 7 8
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • 2 Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • 3 Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
  • 4 Department of Obstetrics and Gynecology, Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China.
  • 5 Greehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • 6 Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA. vadlamudi@uthscsa.edu.
  • 7 Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA. vadlamudi@uthscsa.edu.
  • 8 Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, 78229, USA. vadlamudi@uthscsa.edu.
PMID: 37199805 DOI: 10.1007/s10549-023-06958-4
Abstract

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.

Keywords

PELP1; Ribosome; Rix complex; SMIP34; TNBC.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-159613
    PELP1 Inhibitor