CARD14 Signalling Ensures Cell Survival and Cancer Associated Gene Expression in Prostate Cancer Cells

Abstract

Prostate cancer (PCa) is one of the most common cancer types in men and represents an increasing global problem due to the modern Western lifestyle. The signalling adapter protein CARD14 is specifically expressed in epithelial cells, where it has been shown to mediate NF-κB signalling, but a role for CARD14 in carcinoma has not yet been described. By analysing existing cancer databases, we found that CARD14 overexpression strongly correlates with aggressive PCa in human patients. Moreover, we showed that CARD14 is overexpressed in the LNCaP PCa cell line and that knockdown of CARD14 severely reduces LNCaP cell survival. Similarly, knockdown of BCL10 and MALT1, which are known to form a signalling complex with CARD14, also induced LNCaP cell death. MALT1 is a paracaspase that mediates downstream signalling by acting as a scaffold, as well as a protease. Recent studies have already indicated a role for the scaffold function of MALT1 in PCa cell growth. Here, we also demonstrated constitutive MALT1 proteolytic activity in several PCa cell lines, leading to cleavage of A20 and CYLD. Inhibition of MALT1 protease activity did not affect PCa cell survival nor activation of NF-κB and JNK signalling, but reduced expression of cancer-associated genes, including the cytokine IL-6. Taken together, our results revealed a novel role for CARD14-induced signalling in regulating PCa cell survival and gene expression. The epithelial cell type-specific expression of CARD14 may offer novel opportunities for more specific therapeutic targeting approaches in PCa.

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD‐CC protein family

“…Human germ line and somatic mutations in CARD10 have been suggested to be associated to immunodeficiency, autoimmunity, cancer, cognitive defects, and primary open-angle glaucoma (POAG), but it is not established whether the mutations are activating or inactivating [39][40][41]. High expression of CARD10 or CARD14 have both been associated to increased cancer cell survival [42,43]. Germ line activating mutations in CARD-CC proteins have up until now only been found in CARD11, which result in B cell lymphomas and B cell expansion with NF-jB and T cell anergy (BENTA) [44,45], as well as CARD14, which result in CAPE (CARD14-Associated Papulosquamous Eruption)-a disease spectrum that includes psoriasis and Pityriasis rubra pilaris (PRP) [46,47].…”

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD-CC protein family

“…Human germ line and somatic mutations in CARD10 have been suggested to be associated to immunodeficiency, autoimmunity, cancer, cognitive defects and primary open-angle glaucoma (POAG), but it is not established whether the mutations are activating or inactivating [39–41]. High expression of CARD10 or CARD14 have both been associated to increased cancer cell survival [42,43]. Germ line activating mutations in CARD-CC proteins have up until now only been found in CARD11, which result in B cell lymphomas and B cell expansion with NF-κB and T cell anergy (BENTA) [44,45], as well as CARD14, which result in CAPE ( CARD14 – Associated Papulosquamous Eruption) – a disease spectrum that includes psoriasis and Pityriasis rubra pilaris (PRP) [46,47].…”

CARMA3: A potential therapeutic target in non-cancer diseases

“…CARMA2 mutations are associated with inflammatory skin disorders, especially psoriasis ( 12 ). In cancer cells, CARMA2 knockout leads to inhibition of cell proliferation and migration and decrease in cell survival ( 13 , 14 ). The function of CARMA3 is similar to that of other CARMA proteins, it mediates GPCRs- and RTKs-induced signaling pathways, which are linked to human disease pathogenesis.…”