Abstract 590: RARRES1 is a modulator of angiogenesis and autophagy
Authors: Roy Arpita , Kim Okjin Jean , Ramalinga Malathi , Lynch Solomon , Byers Stephen , Kumar Deepak 
Published: May 2015

Retinoic Acid Receptor Responder (RARRES1) is a putative tumor suppressor gene that exerts its tumor suppressor function via unknown mechanisms. Determining the molecular mechanisms involved in the function of RARRES1 in important biological processes, angiogenesis and autophagy, is the focus of our study and may delineate molecular targets for therapeutic intervention.

Angiogenesis, the formation of new blood vessels from pre-existing vessels, is a vital requirement for the growth and metastasis of tumors. It constitutes a pivotal step in cancer progression. For the tumors to grow and have the propensity to metastasize they have to undergo the “angiogenic switch”. This switch depends on the dynamic balance between the pro-angiogenic factors (such as HIF-1α and VEGF) and the anti-angiogenic factors (such as thrombospondin, VEGI). Stimuli for angiogenesis include hypoxia, inflammation or genetic variations in tumor suppressors. We sought to determine if RARRES1 expression could modulate angiogenesis. Our results indicate that overexpression of RARRES1 in HUVECs severely impairs in vitro angiogenesis. The data also indicate reduced levels of angiogenic markers and signaling molecules, phospho-VEGF-R and phospho-p38 MAPK. The results demonstrate that RARRES1 expression significantly lowers H2O2-induced ROS production, a known inducer of angiogenesis.

Bioinformatics searches of RARRES1 revealed a potential MAPK binding site, the Erk-D domain and multiple PKC phosphorylation sites. PKC signaling (ERK phosphorylation) has been implicated in cellular autophagy. It is an evolutionarily conserved self-degradative process that plays a housekeeping role by eliminating damaged organelles and misfolded or aggregated proteins via the lysosomal degradation pathway. Deregulation of autophagy has been reported in various cancers. Interestingly, our data indicates that RARRES1 expression induces phospho-ERK in multiple cancer cell lines. We hypothesized that the increased phospho-ERK levels in RARRES1 expressing cells would result in autophagy induction. Our results demonstrate that RARRES1 expression induces the expression of autophagy markers, ATG3, beclin and LC-3β.

In summary, the data presented here indicate that (a) loss of RARRES1 results in increased ROS production and angiogenesis by p38 MAPK activation and (b) autophagy defects in RARRES1-deficient cancer cells facilitates tumor progression. Our study implicates that RARRES1 may be a novel anti-angiogenic molecule that induces autophagic response. Future studies will determine the mechanism between these important cell-biological processes and if RARRES1 may serve as a target for therapeutic intervention both in cancer and in angiogenesis-related disorders.

Citation Format: Arpita Roy, Okjin Jean Kim, Malathi Ramalinga, Solomon Lynch, Stephen Byers, Deepak Kumar. RARRES1 is a modulator of angiogenesis and autophagy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 590. doi:10.1158/1538-7445.AM2014-590