Inflammasomes and colorectal cancer: New insights in probiotics

Abstract

Introduction: Colorectal cancer remains among the leading causes of cancer death across the globe. Unfortunately, its management following the standard chemotherapy is not completely satisfying and an alternative therapeutic approach to reduce the related mortality and morbidity could be to arrest or delay the process of carcinogenesis by using alternate biotherapeutic chemotherapeutic agents such as probiotics. Probiotics are defined as "viable non-pathogenic microorganisms, which confer health benefits to the host". Several strains belonging to Lactobacilli and Bifidobacteria have been shown to have anti-carcinogenic effects. Method(s): The present study was designed to evaluate the therapeutic potential of indigenous probiotic Lactobacillus plantarum CRD7 on the cell proliferation, activation of inflammasomes (NLRP3, NLRC4, NAIP5) and mediators of inflammation (IL-18, IL-1b, NF-kB, Ik-B, caspase-1, TLR9 and cGAS) in three differently graded human colon cancer cell lines (namely HT-29, HCT-116, and SW-480) using MTT test and Realtime PCR at 24 h, 48 h and 72 h of treatment with live and heat-killed bacteria. Lactobacillus plantarum CRD7, an indigenous probiotic strain was obtained as generous gift from Dr. Chand Ram, Principal scientist at Division of Dairy Microbiology, National Dairy Research Institute, Karnal, Haryana, India. Result(s):Our results shows that L. plantarumCRD7 has the therapeutic potential in the activation of host derived factors such as inflammasomes and suppressing mediators of inflammation in HT-29,HCT-116 and SW480 cell lines of colorectal cancer. Treatment probiotic Lactobacillus plantarumCRD7 activates the NLRP3 inflammasome. NLRP3 activation leads to the production of IL-18 and IL-1b, which may participate in the regulation of intestinal inflammation and colorectal carcinogenesis. As evident fromour results that cellular interactions of probiotic bacteria occur through TLR9 with a subsequent activation of NF-kB in a time dependent manner which leads to Ik-B dependent phosphorylation of Ik-b and subsequent degradation of Ik-B by the ubiquitin proteasome pathway. As evident fromour results that treatment of live probiotic bacteria significantly upregulated themRNAexpression of TLR9 and cGAS at all the time points of experimental set up which could also leading to the activation of NF-kB, inflammasome, and interferon signaling pathways, respectively. Based on our results, TLR-9 mediated recognition of probiotic bacteria and its components in the human colon cancer cells exerts a protective effect against inflammation. Furthermore, the therapeutic effects of the probiotic Lactobacillus plantarumCRD7 totally diminished with the heat-killed treatment at all time points in three human graded HT-29,HCT-116 andSW480 cell lines. Conclusion(s): Our study shows that indigenous probiotic Lactobacillus plantarumCRD7 froma therapeutic point of view could be used in a future personalized functional food strategy for chemoprevention and cancer growth inhibition as evident fromenhanced anti-proliferative efficacy in three human graded cell lines of colorectal cancer.