Description

The Leukocyte Chemoattractant Chemerin Upregulates PTEN via CMKLR1 in Human Cancers

Keith Rennier, Robert Crowder, Ping Wang, Russell Pachynski*

Division of Oncology, Department of Medicine, Washington University, St Louis, MO

Division of Oncology, Department of Medicine, Washington University, St Louis, MO

Recent data in preclinical models has shown that phosphatase and tensin homolog (PTEN) loss correlated with decreased tumor immune cell infiltration as well as decreased response to T cell-based immunotherapy. Chemerin (RARRES2) is a recently identified endogenous leukocyte chemoattractant shown to recruit innate immune cells through its G-protein coupled receptor CMKLR1. Chemerin/RARRES2 is commonly downregulated in many cancers compared to their normal tissue counterparts. Our previous preclinical studies showed that forced overexpression of chemerin in tumors was capable of recruiting immune effector cells – including T cells - into the tumor microenvironment and suppressing tumor growth. In order to study the effects of chemerin overexpression on tumor cell intrinsic processes we exposed tumor lines to exogenous recombinant chemerin in vitro. Evaluation of PTEN was performed at both the mRNA and protein levels, using both quantitative PCR as well as Western blotting. In vitro invasion assays were performed to investigate the functional impact of chemerin exposure on tumor intrinsic activity. Using both prostate and sarcoma tumor lines, we found exogenous chemerin was able to significantly upregulate PTEN expression at both the mRNA and protein levels in a dose-response manner. Exposure to chemerin did not result in increased apoptosis or altered in vitro proliferation. Importantly, chemerin treatment significantly decreased in vitro tumor invasion. Knockdown studies showed CMKLR1 abrogation resulted in restored tumor migration, suggesting a link between this GPCR and PTEN expression and activity. For the first time, to our knowledge, we have shown a link between chemerin and PTEN expression and activity in both prostate and sarcoma tumor lines. This work has functional implications on both tumor cell intrinsic and extrinsic responses to chemerin-based immunotherapeutic strategies.