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

Abstract

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 PGE 2 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. What's new? Prostaglandin E2 (PGE2) helps cancers grow, but stopping the COX-2 pathway that produces it, without generating harmful side effects, has been challenging. In this paper, the authors looked at the effects of blocking the enzyme microsomal PGE synthase 1 (mPGES-1). Previous experiments have returned mixed reports of whether mPGES-1 boosts tumors. The authors employed the technique of growing tumor cells in multicellular tumor spheroids (MCTS), which better mimics the condition of growth within a living organism than growing them in suspension. They found that while lack of mPGES-1 didn't faze tumor cells grown in monolayer, it did slow the growth of the MCTS, indicating that tumors growing within an animal probably depend on the enzyme. © 2013 UICC.