作者: Pratap, Uday P. ; Yang, Xue ; Lai, Zhao ; Nassar, Khaled Mohamed ; Chen, Yidong ; Sareddy, Gangadhara R. ; Mahajan, Megharani ; Sun, Lu-Zhe ; Adeniran, Timilehin T. ; Viswanadhapalli, Suryavathi ; Baker, Adriana ; Vadlamudi, Ratna K. ; Gopalam, Rahul ; Hernandez Fernandez, Marian H. ; Arnold, William C.

AbstractHepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the United States, with a median survival period of approximately 10 months. There is an urgent need for the development of effective targeted therapies for the treatment of HCC. Proline-, glutamic acid–, and leucine-rich protein 1 (PELP1) signaling is implicated in the progression of many cancers, although its specific contribution to the progression of HCC is not yet well understood. Analysis of The Cancer Genome Atlas HCC gene expression data sets and IHC analysis of HCC tissue microarray revealed that HCC tumors had elevated expression of PELP1 compared with normal tissues, and high expression of PELP1 is associated with unfavorable survival outcomes. Suppression of PELP1 expression using short hairpin RNA significantly reduced the cell viability, clonogenicity, and invasion of HCC cells. Importantly, SMIP34, a first-in-class small-molecule inhibitor targeting PELP1, effectively decreased the cell viability, clonogenic survival, and invasiveness of HCC cells. Gene expression analysis using RNA sequencing revealed that PELP1 knockdown cells exhibited a decrease in c-Myc, E2F, and other oncogenic pathways related to HCC. Mechanistic studies showed that SMIP34 treatment impaired the Rix complex, a critical component of ribosomal biogenesis, in HCC cells. Furthermore, the knockdown or pharmacologic inhibition of PELP1 significantly decelerated the HCC tumor growth in xenograft models. In summary, our study findings indicate that PELP1 could serve as a promising target for therapeutic intervention in HCC.Significance:HCC is one of the leading causes of cancer fatalities in the United States. Effective targeted therapeutics for HCC are urgently needed. In this study, we show that PELP1 proto-oncogene is crucial to HCC progression and that PELP1 inhibition reduced HCC cell proliferation in vitro and in vivo. Our results imply that PELP1-targeted drugs like SMIP34 may be useful as new therapeutic agents for HCC treatment.

2023-07-01·Breast cancer research and treatment

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

Article

作者: Liu, Junhao ; Vadlamudi, Ratna K ; Sanchez, John R ; Sareddy, Gangadhara R ; Yang, Xue ; Altwegg, Kristin A ; Viswanadhapalli, Suryavathi ; Pratap, Uday P ; Li, Xiaonan ; Panneerdoss, Durga Meenakshi ; Rao, Manjeet K ; Ebrahimi, Behnam ; Liu, Zexuan

PURPOSETriple-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.METHODSTo 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.RESULTSTNBC 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.CONCLUSIONSTogether, 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.

2022-10-17·Cancer Research

A First-in-Class Inhibitor of ER Coregulator PELP1 Targets ER+ Breast Cancer

Article

作者: Huang, Tim H.-M. ; Raj, Ganesh V. ; Krishnan, Samaya ; Chen, Yidong ; Pratap, Uday P. ; Viswanadhapalli, Suryavathi ; McHardy, Stan ; Mann, Monica ; Chakravarty, Dimple ; Li, Xiaonan ; Ma, Shihong ; Santhamma, Bindu ; Zhou, Daohong ; Ebrahimi, Behnam ; Lai, Zhao ; Vadlamudi, Ratna K. ; Liu, Zexuan ; Tekmal, Rajeshwar R. ; Yuan, Yaxia ; Altwegg, Kristin A. ; Park, Ben H. ; Vankayalapati, Hariprasad ; Sareddy, Gangadhara R. ; Liu, Junhao ; Sanchez, John R. ; Rao, Manjeet K.

AbstractMost patients with estrogen receptor alpha–positive (ER+) breast cancers initially respond to treatment but eventually develop therapy resistance with disease progression. Overexpression of oncogenic ER coregulators, including proline, glutamic acid, and leucine-rich protein 1 (PELP1), are implicated in breast cancer progression. The lack of small molecules that inhibits PELP1 represents a major knowledge gap. Here, using a yeast-two-hybrid screen, we identified novel peptide inhibitors of PELP1 (PIP). Biochemical assays demonstrated that one of these peptides, PIP1, directly interacted with PELP1 to block PELP1 oncogenic functions. Computational modeling of PIP1 revealed key residues contributing to its activity and facilitated the development of a small-molecule inhibitor of PELP1, SMIP34, and further analyses confirmed that SMIP34 directly bound to PELP1. In breast cancer cells, SMIP34 reduced cell growth in a dose-dependent manner. SMIP34 inhibited proliferation of not only wild-type (WT) but also mutant (MT) ER+ and therapy-resistant breast cancer cells, in part by inducing PELP1 degradation via the proteasome pathway. RNA sequencing analyses showed that SMIP34 treatment altered the expression of genes associated with estrogen response, cell cycle, and apoptosis pathways. In cell line–derived and patient-derived xenografts of both WT and MT ER+ breast cancer models, SMIP34 reduced proliferation and significantly suppressed tumor progression. Collectively, these results demonstrate SMIP34 as a first-in-class inhibitor of oncogenic PELP1 signaling in advanced breast cancer.Significance:Development of a novel inhibitor of oncogenic PELP1 provides potential therapeutic avenues for treating therapy-resistant, advanced ER+ breast cancer.

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