Colorectal cancer (CRC) is the third leading cause of cancer related mortality, world-wide. Gut bacterial dysbiosis is known to be one of the major causes of CRC onset and development. Gut microbiota derived metabolites, e.g. folate and butyrate play crucial roles in cancer initiation, progression, and treatment, and thus, need to be considered for effective CRC management. A potential nanoparticle-based cancer therapy (nanomedicine), involving silver nanoparticles (AgNPs), can impart cytotoxic effects in cancer cells by inducing high intracellular reactive oxygen species (ROS) levels. However, the simultaneous interactions of AgNPs with gut microbiota to aid in CRC treatment has not been reported thus far. Therefore, in this study, the variation in the viability and intracellular ROS concentrations, in Enterococcus durans (E. durans), a representative gut microbe, was studied in the presence of low AgNP concentrations (25 ppm). Upon exposure to AgNPs, the intracellular hydroxyl radical concentrations showed an increase by 48% at the 9th hour of microbial growth. Moreover, folate plays a significant role in maintaining the genetic integrity of the cells. Hence, it was essential to investigate the effects of oxidative stress on folate status and cell viability of the gut microbe. Upon exposure to low concentration of AgNPs, the extracellular folate concentrations also increased by 52% (at 9th hour), thereby implying the involvement of increased oxidative stress in increasing the folate levels. Interestingly, the cell viability reduced with lowered folate levels in the cell. Given its importance in cancer cell growth and proliferation, the cytotoxic property of folic acid was then experimentally studied on HCT116 (a colon cancer cell line). Folic acid, at lower concentrations showed cytotoxic effects on the cancer cell line (reduction in cell viability by 13%), which was unanticipated, and therefore ascertained the cytotoxic potential of folic acid.
Further, to gain a systems level understanding of ROS metabolism in E. durans, COBRA toolbox modeling strategy was adopted. The in-silico modeling reconfirmed the critical association between ROS and increased folate metabolism. Further, amino acids, energy pathways associated metabolites, nucleotides, and butyrate (a short chain fatty acid) were found to be the key players in enhancing the generation of folate derivatives. Since gut microbes are known to interact with the host tissues, via metabolic and signaling pathways, it was crucial to study the interactions between the CRC and gut microbe using the constraint-based modeling (CBM) approach.
To do so, colon and CRC context-specific models were generated using patient-specific proteomics data and literature-based information to highlight the underlying metabolic factors associated with cancer-specific phenotypes. Interestingly, these context-specific metabolic models were able to capture aberrant metabolism in CRC, as established in literature. The metabolic associations between the gut microbe and CRC metabolic models were also studied. Here, we were able to suggest the inter-relationship between CRC and gut microbe (the latter exposed to oxidative stress), and the effects of gut bacterial metabolites on CRC metabolism. These interaction studies can prove substantial in discovering novel targets and metabolites with anti-cancer attributes, to design robust and effective cancer therapies.
Publications:
1. Oxidative stress decreases the redox ratio and folate content in the gut microbe, Enterococcus durans (MTCC 3031), Scientific Reports, Jose, S., Bhalla, P., and Suraishkumar, G. K. (2018), Vol. 8, Article no. 12138, Open Access
2. Silver nanoparticle induced oxidative stress augments anticancer gut bacterial metabolites production; Prerna Bhalla, Raghunathan Rengaswamy, D Karunagaran, GK Suraishkumar, Swagatika Sahoo (2019) doi: https://urlprotection-tko.global.sonicwall.com/click?PV=1&MSGID=202008210709370173796&URLID=14&ESV=10.0.6.3447&IV=65EF5C7B8A831548B85CA1D9846B5D45&TT=1597993779620&ESN=8ukaRdHKzATXRBVrnprK52pF7xI5B4wFVQA6NKoVzJQ%3D&KV=1536961729279&ENCODED_URL=https%3A%2F%2Fdoi.org%2F10.1101%2F658609&HK=E660DD8882855B273B10E514358A466BDDA5BA93F04C5EE25C4B23AA9D9C0CEE (bioRxiv pre-print)
3. Identification of reactive oxygen species therapeutic potential for colorectal cancer: Genome-scale modeling of host-microbe interaction; Prerna Bhalla, Raghunathan Rengaswamy, D Karunagaran, GK Suraishkumar, Swagatika Sahoo (2020) (under review)
4. Constraint-Based Modeling to Understand ROS-Mediated Effects in Cancer (Book chapter); Prerna Bhalla, Swagatika Sahoo, Raghunathan Rengaswamy, Devarajan Karunagaran and G. K. Suraishkumar (2020), Handbook of Oxidative Stress in Cancer, Springer
Link:
meet.google.com/xvu-ebpi-siw