Effects of Maackia amurensis seed lectin (MASL) on oral squamous cell carcinoma (OSCC) gene expression and transcription
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ORIGINAL ARTICLE – CANCER RESEARCH
Effects of Maackia amurensis seed lectin (MASL) on oral squamous cell carcinoma (OSCC) gene expression and transcriptional signaling pathways Kelly L. Hamilton1 · Stephanie A. Sheehan1 · Edward P. Retzbach1 · Clinton A. Timmerman1 · Garret B. Gianneschi1 · Patrick J. Tempera1 · Premalatha Balachandran2 · Gary S. Goldberg1 Received: 9 September 2020 / Accepted: 5 November 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose Oral cancer causes over 120,000 deaths annually and affects the quality of life for survivors. Over 90% of oral cancers are derived from oral squamous cell carcinoma cells (OSCCs) which are generally resistant to standard cytotoxic chemotherapy agents. OSCC cells often exhibit increased TGFβ and PDPN receptor activity compared to nontransformed oral epithelial cells. Maackia amurensis seed lectin (MASL) can target the PDPN receptor and has been identified as a novel agent that can be used to treat oral cancer. However, mechanisms by which MASL inhibits OSCC progression are not yet clearly defined. Methods Here, we performed cell migration and cytotoxicity assays to assess the effects of MASL on OSCC motility and viability at physiologically relevant concentrations. We then performed comprehensive transcriptome analysis combined with transcription factor reporter assays to investigate the how MASL affects OSCC gene expression at these concentration. Key data were then confirmed by western blotting to evaluate the effects of MASL on gene expression and kinase signaling activity at the protein level. Results MASL significantly affected the expression of about 27% of approximately 15,000 genes found to be expressed by HSC-2 cells used to model OSCC cells in this study. These genes affected by MASL include members of the TGFβ–SMAD, JAK–STAT, and Wnt–βCTN signaling pathways. In particular, MASL decreased expression of PDPN, SOX2, and SMAD5 at the RNA and protein levels. MASL also inhibited SMAD and MAPK activity, and exhibited potential for combination therapy with doxorubicin and 5-fluorouracil. Conclusions Taken together, results from this study indicate that MASL decreases activity of JAK–STAT, TGFβ–SMAD, and Wnt–βCTN signaling pathways to inhibit OSCC growth and motility. These data suggest that further studies should be undertaken to determine how MASL may also be used alone and in combination with other agents to treat oral cancer. Keywords Oral cancer · Oral squamous cell carcinoma · Chemotherapy · Maackia amurensis · Lectin · Podoplanin · Tgfβ · SMAD · JAK–STAT
Introduction
* Gary S. Goldberg [email protected] 1
Department of Molecular Biology, Science Center, Graduate School of Biomedical Sciences, School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USA
National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA
2
Over 400,000 new oral cancer cases are diagnosed each year, causin
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