Abstract LB-337: Protection against tumor growth by disruption of adenylyl cyclase type 5 (AC5).

Abstract

Abstract Adenylyl cyclase (AC) catalyzes the conversion of ATP to the second messenger cAMP, which in turn activates protein kinase A (PKA). AC/cAMP/PKA signaling pathway is known to mediate tumor growth but the results of previous studies have been controversial. More importantly, little is known about how specific AC isoforms affect tumor growth. Based on our previous data showing that knocking out the isoform AC type 5 in mice (AC5KO) extends longevity and that the major cause of premature mortality in mice is neoplastic diseases, we hypothesized that AC5KO mice can be protected against tumor growth. We previously demonstrated that AC5KO mice are protected against oxidative stress and obesity, which should also provide protection against neoplastic disease. In order to elucidate whether AC5 plays a role in the tumor microenvironment, we initially investigated the growth of B16F10 melanoma in this model. We have found that AC5KO mice exhibit protection against B16F10 melanoma tumor growth (p<0.01). Tumor latency, wet tumor weights and tumor volume were also significantly reduced in AC5KO mice (p<0.01). At day 27, tumor volumes were significantly lower (p<0.01) (AC5KO mice: 500.30±119 vs. WT: 2692.28±508 mm3). Tumors from AC5KO mice had a 68% decrease in cell proliferation index and AC5HET mice had a 37% both with respect to the WT (p<0.01 and p<0.05 respectively). Also, tumors from AC5KO mice displayed a significantly larger apoptotic rate compared to the AC5WT (2.30±0.48% vs. 1.00±0.20 %, p<0.05). Ablation of AC5 in mice also leads to a significantly lower intra-tumor microvessel density (AC5HET: 8±0.4 and AC5KO: 6.2±0.6 compared to WT: 11.5±0.9; p<0.05 and p<0.01).In addition, AC5KO mice had significantly lower VEGF serum levels than WT mice (AC5KO: 2.5±0.1 vs. AC5WT: 3.3±0.2 ng/ml; p<0.05). Tumors in AC5KO mice induced significantly lower angiogenic response than in WT mice, as measured by total vessel length (AC5KO: 58.7±6.2 vs. WT: 100± 8.5, p<0.001). Obesity is a risk factor for the development of breast cancer. In accord with the fact that AC5KO are protected against obesity, we have found that circulating levels of leptin were significantly reduced in AC5KO: 1.99±0.28 vs. WT: 3.23±0.35 ng/ml (p<0.05). In an attempt to elucidate the role of the stromal AC5 isoform and the connection between the AC5KO protection against obesity and tumor incidence; we crossbred AC5 mice with MMTV Her 2 neu mice; a model prone to develop mammary tumors. We have found that AC5KO x MMTV HER-2 neu mice weighed significantly less (p<0.001) and had a significantly lower mammary tumor incidence (p<0.05). All these results together show that understanding the mechanism underlying the role of AC5 in regulating tumor growth and its anti-tumor properties will have a profound impact on its potential therapeutic application as a target for anticancer drug development. Citation Format: Mariana S. De Lorenzo, Wen Y. Chen, Erdene Baljinnyam, Krista La Perle, Sanford P. Bishop, Thomas E. Wagner, Patricio Abarzua, Arnold B. Rabson, Dorothy E. Vatner, Lydia I. Puricelli, Stephen F. Vatner. Protection against tumor growth by disruption of adenylyl cyclase type 5 (AC5). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-337. doi:10.1158/1538-7445.AM2013-LB-337