Inhibition of the Activity of Cyclophilin A Impedes Prolactin Receptor-Mediated Signaling, Mammary Tumorigenesis, and Metastases

Abstract

Summary Prolactin (PRL) and its receptor (PRLr) play important roles in the pathogenesis of breast cancer. Cyclophilin A (CypA) is a cis-trans peptidyl-prolyl isomerase (PPI) that is constitutively associated with the PRLr and facilitates the activation of the tyrosine kinase Jak2. Treatment with the non-immunosuppressive prolyl isomerase inhibitor NIM811 or CypA short hairpin RNA inhibited PRL-stimulated signaling, breast cancer cell growth, and migration. Transcriptomic analysis revealed that NIM811 inhibited two-thirds of the top 50 PRL-induced genes and a reduction in gene pathways associated with cancer cell signaling. In vivo treatment of NIM811 in a TNBC xenograft lessened primary tumor growth and induced central tumor necrosis. Deletion of CypA in the MMTV-PyMT mouse model demonstrated inhibition of tumorigenesis with significant reduction in lung and lymph node metastasis. The regulation of PRLr/Jak2-mediated biology by NIM811 demonstrates that a non-immunosuppressive prolyl isomerase inhibitor can function as a potential breast cancer therapeutic.

Serine residues 726 and 780 have nonredundant roles regulating STAT5a activity in luminal breast cancer

“…WT-STAT5a PRL-induced or inhibited genes were compared to previous PRL-transcriptomic data released by our laboratory, such that after matching the criteria that the DEG be present in at least two datasets, 105 putative PRL-regulated genes were identified (Supplemental Table S4 ) 38 , 39 . A subset of these genes were used to identify functionally-enriched pathways with PRL treatment that may be changed by expression of the STAT5a mutants through Ingenuity Pathway Analysis (IPA, Qiagen, Fig.…”

The Relevant Participation of Prolactin in the Genesis and Progression of Gynecological Cancers

“…In a phase I clinical trial, the monoclonal antibody LFA102, a humanized neutralizing monoclonal antibody directed against the extracellular domain of PRLR, was tested in patients with advanced BC (10), which had previously caused tumor shrinkage in an in vivo model of BC (11). In vitro and in vivo, preclinical reports suggest that the PRL-PRLR union is vital for breast carcinogenesis (9,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). However, in the clinical area, LFA102 had no anti-tumor effect when administered as a single agent in patients with PRLRpositive metastatic BC, questioning the role of PRL in the development of BC and highlighting the need for further studies to fully understand the role of PRLR-driven signaling cascades in tumor growth (10).…”

“…PRL promotes the initiation and progress of different gynecological neoplasms through different mechanisms. Furthermore, it is known that they share the cellular effects exerted through the JAK/STAT signaling cascade, such as survival, cell cycle progression, proliferation, migration, high metabolic rates, angiogenesis, and anti-apoptosis (9,12,(29)(30)(31)(32)(33)(34)(35)(36). In addition to this, it has been found that the PRLR is overexpressed in breast (14,37), cervical (38)(39)(40), ovarian (41,42), and endometrial cancer (EC) (2,43) in comparison with their respective cancer-free tissues.…”

“…Migration is an essential cellular event that allows cancer cells to move towards new anatomical niches to generate secondary tumors, an action known as metastasis ( 12 , 15 ). To achieve this, a reorganization of the actin cytoskeleton must be performed by the cell, and it is known that members of the RHO family of small GTPases, such as RAC, RHO, and CDC42 proteins, are essential controllers of cytoskeleton dynamics ( 50 , 51 ).…”

Identification Of PPIA As A Prognostic Biomarker Of Lung Adenocarcinoma From Bioinformatics Analysis

“…Moreover, this enzyme has been shown to be a key molecule in multiple biological functions, including molecular chaperoning,protein folding,protein tra cking,immune modulation,and cell signaling [6]. Studies have also reported that PPIA is involved in several diseases, including kawasaki disease [7],amyotrophic lateral sclerosis [8],atherosclerosis,myocardial infarction [9],severe sepsis [10],vascular smooth muscle cell disease [11],rheumatoid arthritis and HIV infection [12].Moreover,several studies have shown that PPIA is expressed in some cancers,including lung cancer,nasopharyngeal carcinoma [13],gastric adenocarcinoma [14],thyroid carcinoma [15],neuroblastoma [16],ovarian cancer [17],pancreatic cancer [18],breast cancer,colorectal cancer [19][20],melanoma [21],liver hepatocellular carcinoma [22].Many researchers have assessed PPIA function in cancer.It has been suggested that PPIA plays an important role in the whole pathological process of cancer development.High expression levels of PPIA were associated with decreased overall survival in liver hepatocellular carcinoma,colorectal cancer,low-grade glioma, acute myeloid leukemia.However,in gastric adenocarcinoma, high expression levels of CypA are positively correlated with invasiveness and distant metastasis.Therefore,both low and high expression of PPIA are associated with tumor prognosis.…”