The effects of pi3k and pkc subtypes in resistance to the anti-tumor effects of CXC chemoki̇ne receptor 2 antagonists in metastatic breast cancer

Objective: CXC chemokines and its receptors play an important role in the development of cancer. CXC chemokine receptor 2 (CXCR2) is expressed by many cancer cells and its activation plays a role in metastasis. Therefore, CXCR2 antagonists in treatment of cancer is promising. MIP-2 (CXCL2) and KC (CXCL1), two important ligands of CXCR2 play a role in angiogenesis and tumor progression by causing infiltration of immunosuppressive cells, especially neutrophils. In our previos study we found that, CXCR2 antagonist SB225002 inhibits proliferation of breast cancer cells but also increases MIP-2 was detected. This suggested that CXCR2 is an autoreceptor for its ligands and that resistance can develop with chronic antagonist treatment. The aim of this study was to investigate the possible mechanisms of increased chemokine secretion which may lead resistance to treatment. Method: The effects of PI3Kβ and α subtypes-specific inhibitors (TGX221, GSK2636771 and BYL719) and PKCɛ activator (FR236924) alone and in combination with the CXCR2 antagonist were determined on the proliferation of brain (4TBM) and heart (4THM) metastatic breast cancer cells usintg the WST-1 method. Changes in MIP-2 and KC secretions were determined by ELISA method. The effects on phosphorylation of AKT, ERK and P38 proteins were investigated by western blot method. Results: PI3Kα inhibitor showed strong antitumorogenic effect. It significantly reduced the increase in MIP-2 and KC release due to CXCR2 antagonist. AKT phosphorylation was completely suppressed by PI3Kα inhibition. No significant effect of PI3Kβ inhibition was observed. The relatively high concentration of PKCɛ activator (10µM) suppressed the proliferation of cancer cells and partially inhibited the increase in MIP-2 and KC release in 4TBM. Conclusion: These results demonstrated for the first time that the PI3Kα / AKT pathway may play a role in the possible resistance to the use of chronic CXCR2 antagonist in metastatic breast cancer. Hence the combination of CXCR2 inhibitors with specific PI3Kα inhibitor may increase the anti-tumorogenic effects of CXCR2 antagonists.