C5aR deficiency attenuates the breast cancer development via the p38/p21 axis

Abstract

Emerging evidence has shown activation of the complement component C5 to C5a in cancer tissues and C5aR expression in breast cancer cells relates to the tumor development and poor prognosis, suggesting the involvement of complement C5a/C5aR pathway in the breast cancer pathogenesis. In this study, we found that as compared to the non-tumoral tissues, both C5aR and MAPK/p38 showed an elevated expression, but p21/p-p21 showed lower expression, in the tumoral tissues of breast cancer patients. Mice deficient in C5aR or mice treated with the C5aR antagonist exhibited attenuation of breast cancer growth and reduction in the p38/p-p38 expression, but increase in p21/p-p21 expression, in the tumor tissues. Pre-treatment of the breast cancer cells with recombinant C5a resulted in reduced p21 expression, and MAPK/p38 inhibitors prevented C5a-induced reduction in p21 expression, suggesting the involvement of the MAPK/p38 signaling pathway in the C5a/C5aR-mediated suppression of p21/p-p21 expression. These results provide evidence that breast cancer development may rely on C5a/C5aR interaction, for which MAPK/p38 pathway participate in down-regulating the p21 expression. Inhibition of C5a/C5aR pathway is expected to be helpful for the treatment of patients with breast cancer.

By Increasing the Expression and Activation of STAT3, Sustained C5a Stimulation Increases the Proliferation, Migration, and Invasion of RCC Cells and Promotes the Growth of Transgrafted Tumors

“…27 In cancer cells, C5a reportedly suppresses p21 expression via activation of the PI3K/AKT pathway and thus functions in the pathogenesis of gastric cancer. 28,29 C5a also reportedly increases ZEB1 expression and enhances the invasion of human glioblastoma cells via activation of p38 MAPK. 30 Using C5aR1-transfected mouse RCC cells (Renca cells), Maeda et al reported that C5a elicited cytoskeletal rearrangements and morphological changes in the cells and ultimately increased their invasiveness through activation of the ERK and AKT pathways.…”

Crosstalk between pro-survival sphingolipid metabolism and complement signaling induces inflammasome-mediated tumor metastasis

“…Several studies have now demonstrated that complement molecules, such as C3a/C5a, the anaphylatoxin cleavage fragments, can be produced by tumor cells and utilized to promote angiogenesis, metastasis, and immunosuppression leading to enhanced tumor survival. 54 - 58 Interestingly, in addition to the activation of C3b-α′ 2 , we also observed secretion of C3a in response to S1P/S1PR1 signaling, which seemed to be dependent on CTSL expression and activity. Our data suggest that, while C3b-α′ 2 associates with PPIL1 to activate the inflammasome in tumors to induce metastasis, secreted C3a from tumors can associate with C3aR1 in the TME to exacerbate lung colonization and metastasis.…”

C5aR1 promotes the progression of colorectal cancer by EMT and activating Wnt/β-catenin pathway

“…Recent studies had found that C5aR1 was up-regulated in breast cancer, colon cancer, hepatocellular carcinoma, lung cancer, gastric cancer, kidney cancer, cervical cancer [13,[18][19][20][21]. Up-regulated C5aR1 expression in tumors was usually associated with higher proliferation rate, tumor [11,22].…”