Biology subjects

Padhye, S.

Publications and source records attributed to Padhye, S..

3 recordsLinked to original sources

bioRxiv2022

Design, synthesis and biological evaluation of novel quercetin derivatives as PPAR-γ partialagonists by modulating Epithelial-mesenchymal transition in lung cancer metastasis

Epithelial-to-mesenchymal transition (EMT) is responsible for driving metastasis of multiple cancer types including lung cancer. Peroxisome proliferator-activated receptor (PPAR)-{gamma}, a ligand-activated transcription factor, controls expression of variety of genes involved in EMT, cellular differentiation, fatty acid metabolism, insulin sensitivity and adipogenesis. Several synthetic compounds act as potent full agonist for PPAR-{gamma}. However, owing to their serious adverse effects, restricts their long-term application. Therefore, partial agonist has been greatly in demand which involves reduced and balanced PPAR-{gamma} activity. Our previous study discerned the efficacy of quercetin and its derivatives to attain favourable stabilization with PPAR-{gamma}. Here we extended this work by synthesizing five novel quercetin derivatives (QDs) namely thiosemicarbazone (QUETSC) and hydrazones (QUEINH, QUENH, QUE2FH and QUESH) and analysed their effects in modulating EMT of lung cancer cell lines via PPAR-{gamma} partial activation. QDs-treated A549 cells exhibited cell death strongly in a dose and time dependent manner at nanomolar concentration along with anti-migratory effects compared to NCI-H460 cells. Of the five derivatives we screened, QUETSC, QUE2FH and QUESH exhibited the property of partial activation as compared to the over-expressive level of rosiglitazone (RSG). Consistently, with PPAR-{gamma} partial activation, these QDs also suppressed EMT process by markedly down-regulating the levels of mesenchymal markers (Snail, Slug and Zeb-1) and concomitant up-regulation of epithelial marker (E-cadherin). In the light of these evidences; QUETSC, QUE2FH and QUESH could be used as a novel selective partial PPAR-{gamma} modulators whose pharmacological properties is distinct from RSG and may be exploited as potential therapeutic anti-metastatic agent.

cancer biology↗

bioRxiv2022

Doublecortin like kinase 1 is a target in squamous cell carcinoma

Doublecortin like kinase 1 (DCLK1) plays a crucial role in several cancers including colon and pancreatic adenocarcinomas. However, its role in squamous cell carcinoma (SCC) remains unknown. To this end, we examined DCLK1 expression in head and neck squamous cell carcinoma (HNSCC) and anal squamous cell carcinoma (ASCC). We found that DCLK1 is elevated in patient SCC tissue, which correlated with cancer progression and poorer overall survival. Furthermore, DCLK1 expression is significantly elevated in HPV negative cancer tissues, which are typically aggressive with poor responses to radiation therapy. To understand the role of DCLK1 in tumorigenesis, we used specific shRNA to suppress DCLK1 expression. This significantly reduced tumor growth, spheroid formation, and migration of HNSCC cancer cells. To further the translational relevance of our studies, we sought to identify a selective DCLK1 inhibitor. Current attempts to target DCLK1 using pharmacologic approaches have relied on non-specific suppression of DCLK1 kinase activity. Here, we demonstrate that DiFiD [3,5-bis (2,4-difluorobenzylidene)-4-piperidone] binds to DCLK1 with high selectivity. Moreover, DiFiD mediated suppression of DCLK1 led to G2/M arrest and apoptosis and significantly suppressed tumor growth of HNSCC xenografts and ASCC patient derived xenografts, supporting that DCLK1 is critical for SCC growth.

cancer biology↗

bioRxiv2021

RNA binding protein RBM3 augments kissing loop formation with lncRNAs to enhance translational control

It is becoming apparent that translational regulation involves the coordinated actions of RNA binding proteins (RBPs) and non-coding RNAs. For efficient translation, mRNA needs to be circularized, which is catalyzed by RNA binding proteins and translation factors. However, the role of lncRNAs in the process is not yet defined. We first performed RNA-seq and RNA- immunoprecipitation coupled-Seq and identified LSAMP-3 and Flii-1. Moreover, modeling studies suggest enhanced kissing loop interactions including of transcripts that encode angiogenesis and epithelial mesenchymal transition. While intestinal epithelial cell specific RBM3 transgenic mice showed increased LSAMP-3 and Flii-1, this was reduced in knockout mice. Also, RBM3 overexpression increased tumor xenograft growth, this was suppressed by knockdown of the lncRNAs. Also, knockdown of endogenous RBM3 reduced lncRNA levels and tumor xenograft growth. In addition, it reduced colitis-associated cancers. We propose that RBPs such as RBM3 mediate their function through regulatory lncRNAs that enable circularization to control translation.

cancer biology↗