Chronic inflammation has been considered as an emerging hallmark of cancer. Inflammatory tumor micro-environment is being implicated as a major player that can fuel tumor progression via paracrine stimulation - with activated stellate cells, fibroblasts and in particular infiltrating macrophages. It was shown that macrophages themselves drive the transformation and provide the stage for development of cancer. Proline-, Glutamic acid-, and Leucine-rich protein 1 (PELP1) is a novel nuclear receptor co-regulator that cross-talk with various signaling complexes and its expression is deregulated in several cancers. Despite a large body of evidence linking PELP1 with human cancer, evidence supporting the causative role of PELP1 in inflammatory responses remains unknown. Our results from molecular mechanistic studies utilizing both human and mouse macrophage cell lines, and mouse models showed that PELP1 is an inflammation-inducible gene. The sequence analysis of PELP1 promoter followed by cloning and characterization experiments further suggested that the expression of PELP1 is regulated by an NF-kB transcription factor known as c-Rel. These results were further confirmed by Chromatin Immuno Precipitation assay (ChIP) and Electrophoretic Mobility Shift assay (EMSA). In addition, qPCR-expression profiling of mouse inflammatory pathway genes resulted in the determination of the possible putative target of PELP1 i.e. GM-CSF (Granulocyte Macrophage Colony Stimulating Factor). Here, the findings have demonstrated that the release of GM-CSF increased the expression of PELP1 in epithelial cells which indicated an existence of a dynamic positive feedback loop in the regulation of PELP1 expression. Results from clinical samples with normal-inflammation-tumor progression models further proved an increased expression of PELP1 in a progressive manner that signifies the PELP1 as a connecting link between inflammation and cancer.

Publications:

Geraldine Sandana Mala John, Veena Kumari Vuttaradhi, Satoru Takeuchi, Ravi Shankar Pitani, Ganesh Venkatraman and Suresh Kumar Rayala Facile synthesis and nanoscale features of a nanostructured nordihydroguaiaretic acid analog for therapeutic applications. J Nanobiotechnol 18, 74 (2020).
Kesavan, Akila, P. Ilaiyaraja, W. Sofi Beaula, Vuttaradhi Veena Kumari, J. Sugin Lal, C. Arunkumar, G. Anjana et al. "Tumor targeting using polyamidoamine dendrimercisplatin nanoparticles functionalized with diglycolamic acid and herceptin". Eur. J. Pharm. Biopharm. 96 (2015): 255-263.