Abstract 2203: Regulation of hedgehog signaling by Mixed Lineage Kinase 3 (MAP3K11) in pancreatic cancer

Abstract

Abstract Pancreatic adenocarcinoma (PDA) remains a most deadly malignancy, with less than 5% survival over 5-year. The treatment of PDA is limited due to lack of multiple drug options, however, Gemcitabine which is widely used for PDA, finally develops resistance. Therefore, there is an urgent need to identify new pathways that can alternatively be targeted in PDA. Here we report a novel pathway that promotes oncogenic potential of Gli1, an effector of hedgehog pathway (Hh). We recently reported that MLK3 phosphorylates Pin1 on Ser138 site and increases its catalytic activity and nuclear translocation. In order to identify targets of nuclear p-Pin1, we performed cancer specific gene expression profiling and found 13-fold up-regulation of Gli1 transcript, suggesting MLK3-Pin1-Gli1 axis could activate Hh pathway. Indeed we observed that all three proteins were overexpressed in pancreatic cancer cell lines (Panc-1, MiaPaca2, AsPC-I) compared to epithelial (HPDE) cells. Most importantly, MLK3, pMLK3, Pin1 and Gli1 were overexpressed in human pancreatic cancer tissues, compared to normal adjacent tissues. Expression of Pin1 and Gli1 was also higher in tumors from PDA mouse model (KPC mouse). Interestingly, MLK3 was able to directly phosphorylate Gli1 on specific residues and the transcriptional activity of Gli1 was synergistically regulated by Pin1 and MLK3 together, which was partially blocked by MLK3 pan-inhibitor, CEP-1347. CEP-1347 also down-regulated the expression of sonic hedgehog (Shh) in Panc-1 cells suggesting that MLK3 regulates Gli1 signaling at transcriptional and post-translational levels. These results prompted us to identify the ligand(s) that could activate this axis in PDA. Quite interestingly, while doing cytokine/chemokine profiling, specifically regulated by MLK3, we observed about 7-8 folds up regulation of CXCL5 in the liver of WT mice compared to MLK3 KO mice. CXCL5 up regulation was also found in the pancreas of the WT mice. Furthermore, the MLK3 was activated by CXCL5 in pancreatic cancer cell line and MLK3 kinase activities also directly correlated with the reported expression of CXCL5 in different pancreatic cell lines. In conclusion, our findings suggest that pathological activation of MLK3-Pin1 axis by CXCL5, could promote survival of pancreatic cancer cells via Hh pathway activation. Thus targeting CXCL5-MLK3-Pin1-Gli1 axis might abrogate pancreatic cancer cell growth. This work is supported by VA Grant #: BX000312 (AR) and BX000571 (BR). Citation Format: Navin Viswakarma, Gautam Sondarva, Rajakishore Mishra, Rakesh Sathish Nair, Subhasis Das, Basabi Rana, Ajay Rana. Regulation of hedgehog signaling by Mixed Lineage Kinase 3 (MAP3K11) in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2203. doi:10.1158/1538-7445.AM2015-2203