Necrosis in DU145 prostate cancer spheroids induces COX‐2/mPGES‐1‐derived PGE2 to promote tumor growth and to inhibit T cell activation

Cyclooxygenase (COX)‐2‐derived prostaglandin E2 (PGE₂) supports the growth of a spectrum of cancers. The potential benefit of COX‐2‐inhibiting non‐steroidal anti‐inflammatory drugs (NSAIDs) for cancer treatment is however limited by their well‐known cardiovascular side‐effects. Therefore, targeting microsomal PGE synthase 1 (mPGES‐1), the downstream enzyme in the COX‐2‐dependent pathway of PGE₂ production might be attractive, although conflicting data regarding a potential tumor‐supporting function of mPGES‐1 were reported. We determined the impact of mPGES‐1 in human DU145 prostate cancer cell growth. Surprisingly, knockdown of mPGES‐1 did not alter growth of DU145 monolayer cells, but efficiently inhibited the growth of DU145 multicellular tumor spheroids (MCTS). Opposed to MCTS, monolayer cells did not secrete PGE₂ due to a lack of COX‐2 expression, which was induced during spheroid formation. Pharmacological inhibition of COX‐2 and mPGES‐1 supported the crucial role of PGE₂ for growth of MCTS. The functionality of spheroid‐derived PGE₂ was demonstrated by its ability to inhibit cytotoxic T cell activation. When investigating mechanisms of spheroid‐induced COX‐2 induction, we observed that among microenvironmental factors neither glucose deprivation, hypoxia nor tumor cell apoptosis enhanced COX‐2 expression. Interestingly, interfering with apoptosis in spheroids triggered a shift towards necrosis, thus augmenting COX‐2 expression. We went on to demonstrate that necrotic cells induced COX‐2 mRNA expression and PGE₂ secretion from live tumor cells. In conclusion, necrosis‐dependent COX‐2 upregulation in MCTS promoted PGE₂‐dependent tumor growth and inhibited activated cytotoxic T cells. Hence, blocking mPGES‐1 as a therapeutic option may be considered for COX‐2/mPGES‐1‐positive solid cancers.