Bharti Garg

Modulation of post-translational modifications in β-catenin and LRP6 inhibits Wnt signaling pathway in pancreatic cancer

β-Catenin/Wnt signaling pathway is critically regulated in a normal cell by a number of post-translational modifications. In pancreatic cancer however, aberrant activation of this pathway plays a significant role in tumor progression and metastasis. Though a number of studies have focused on understanding Wnt signaling pathway in pancreatic cancer, there has been no systematic study to evaluate molecules that may be affecting this pathway. In the current study, we used a diterpene triepoxide, triptolide, to inhibit post-translational modifications in Wnt pathway and evaluated how this compound may be affecting the intricate signaling that regulates cell proliferation in pancreatic cancer. Our results showed that triptolide inhibits the activation of WNT1, FZD1, and disheveled (DSH) in pancreatic cancer cell lines MIA PaCa-2 and S2-VP10 by inhibiting the phosphorylation of LRP6 and simultaneously blocked translocation of β-catenin to the nucleus by inhibiting its glycosylation. Additionally, inhibition of post-translational modification of the Wnt-signaling pathway also demonstrated regression of tumor growth in a Syngenic Tumor Implantation Model (STIM). Interestingly, these findings suggest Wnt signaling is a vital molecular pathway in pancreatic cancer and may be amenable to targeted drug therapy.

“Heat shock protein 70 in pancreatic diseases: Friend or foe”

The heat shock response in pancreatitis that is activated via HSP70 protects acinar cells through multiple simultaneous mechanisms. It inhibits trypsinogen activation and modulates NF‐κB signaling to limit acinar cell injury. On the other hand, HSP70 is overexpressed in pancreatic cancer and is hijacked by the cellular machinery to inhibit apoptosis. Inhibition of HSP70 in pancreatic cancer by a novel compound, Minnelide, has shown considerable clinical promise.

Gut Microbiota Promotes Tumor Growth in Mice by Modulating Immune Response

We studied the effects of gut microbiome depletion by oral antibiotics on tumor growth in subcutaneous and liver metastases models of pancreatic cancer, colon cancer, and melanoma. Gut microbiome depletion significantly reduced tumor burden in all the models tested. However, depletion of gut microbiome did not reduce tumor growth in Rag1-knockout mice, which lack mature T and B cells. Flow cytometry analyses demonstrated that gut microbiome depletion led to significant increase in interferon gamma-producing T cells with corresponding decrease in interleukin 17A and interleukin 10-producing T cells. Our results suggest that gut microbiome modulation could emerge as a novel immunotherapeutic strategy.