Abstract
Receptor tyrosine kinase ErbB receptors and the phosphoinositide 3-kinase (PI3K) pathway are frequently mutated and/or aberrantly activated in cancer. On the other hand, they play important roles in regulating the physiological function of the heart. Understanding how ErbB receptors and the PI3K pathway protect the heart from chemotherapy-induced heart failure is important for developing successful treatments in cancer with minimum interference to vital processes in the heart. Our studies have focused on the role of these signaling pathways in mice. First, we used transgenic mice with cardiac myocyte-specific overexpression of a constitutively active PI3K-p110\#945; (CaPI3K), or a dominant negative PI3K-p110\#945; (dnPI3K) in the heart, and monitored survival and evaluated functional responses to a challenge with doxorubicin. Second, we used a pharmacological approach and tested whether neuregulin-1 (NRG1), a ligand for erbB receptors, could alleviate doxorubicin-induced cardiac dysfunction in dnPI3K mice. Methods: We injectedwild type (WT), CaPI3K or dnPI3K mice with a single dose of doxorubicin and analyzed survival by the Kaplan-Meier method, cardiac function by hemodynamic measurements and the activation of signaling molecules by Western blot analysis. Non-treated mice were used as controls. Results: After doxorubicin treatment, survival was improved in CaPI3K-Dox mice compared to WT-Dox mice, but was worsened in dnPI3K-Dox vs. WT-Dox mice. Cardiac function (as measured by LV systolic pressure (LVSP), as well as dP/dtmax and dP/dtmin) was depressed in doxorbucin-treated mice. However, cardiac function was improved significantly in CaPI3K-Dox vs. WT-Dox mice, but was more depressed in dnPI3K-Dox vs. WT-Dox mice. NRG1 treatment improved both survival and cardiac function in dnPI3K mice treated with doxorubicin. Western blot analysis showed that in control mice, the level of phosphorylated Akt was increased in CaPI3K vs. WT hearts, but was decreased in dnPI3K vs. WT hearts. On the other hand, the level of phosphorylated ERK1/2 was slightly decreased in CaPI3K vs. WT hearts, but was increased in dnPI3K vs. WT hearts. In doxorubicin-treated mice, the ratios of pAkt/Akt and pERK/ERK were higher in CaPI3K-Dox vs. WT-Dox hearts. However, there was no difference in the pERK/ERK level between dnPI3K-Dox vs. WT-Dox hearts. The levels of phosphorylated ERK1/2 and phosphorylated S6 in the heart were decreased in dnPI3K mice by treatment with doxorubicin and were restored by NRG1. Conclusions: These results suggest that PI3K is important for protecting the heart from doxorubicin-induced cardiac dysfunction. NRG1 is able to alleviate doxorubicin-induced cardiac dysfunction in hearts that overexpress dnPI3K. These effects of NRG1 may depend on the activations of ERK and mTOR.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4287.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO