PKCσ facilitates lymphatic metastatic spread of prostate cancer cells in a mice xenograft model

Prostate cancer disseminates primarily into the adjacent lymph nodes, which is related to a poor outcome. Atypical protein kinase C sigma (PKC sigma) is highly expressed in aggressive prostate cancer and correlates with Gleason score, clinical stage, and poor prognosis. Here, we report the molecular mechanisms of PKC sigma in lymphatic metastasis during prostate cancer progression. Using zinc-finger nuclease technology or PKC shRNA lentiviral particles, and orthotopic mouse xenografts, we show that PKC sigma-knockout or knockdown from aggressive prostate cancer (PC3 and PC3U) cells, decreasesd tumor growth and lymphatic metastasis in vivo. Intriguingly, PKC sigma-knockout or knockdown impaired the activation of AKT, ERK, and NF-kappa B signaling in prostate cancer cells, thereby impairing the expression of lymphangiogenic factors and macrophage recruitment, resulting in aberrant lymphangiogenesis. Moreover, PKC sigma regulated the expression of hyaluronan synthase enzymes, which is important for hyaluronan-mediated lymphatic drainage and tumor dissemination. Thus, PKC sigma plays a crucial oncogenic role in the lymphatic metastasis of prostate cancer and is predicted to be a novel therapeutic target for prostate cancer.