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Necrosis in DU145 prostate cancer spheroids induces COX-2/mPGES-1-derived PGE2 to promote tumor growth and to inhibit T cell activation.
Int J Cancer. 2013 Oct 01; 133(7):1578-88.IJ

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 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.

Authors+Show Affiliations

Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, Frankfurt, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23536473

Citation

Sha, Weixiao, et al. "Necrosis in DU145 Prostate Cancer Spheroids Induces COX-2/mPGES-1-derived PGE2 to Promote Tumor Growth and to Inhibit T Cell Activation." International Journal of Cancer, vol. 133, no. 7, 2013, pp. 1578-88.
Sha W, Olesch C, Hanaka H, et al. Necrosis in DU145 prostate cancer spheroids induces COX-2/mPGES-1-derived PGE2 to promote tumor growth and to inhibit T cell activation. Int J Cancer. 2013;133(7):1578-88.
Sha, W., Olesch, C., Hanaka, H., Rådmark, O., Weigert, A., & Brüne, B. (2013). Necrosis in DU145 prostate cancer spheroids induces COX-2/mPGES-1-derived PGE2 to promote tumor growth and to inhibit T cell activation. International Journal of Cancer, 133(7), 1578-88. https://doi.org/10.1002/ijc.28181
Sha W, et al. Necrosis in DU145 Prostate Cancer Spheroids Induces COX-2/mPGES-1-derived PGE2 to Promote Tumor Growth and to Inhibit T Cell Activation. Int J Cancer. 2013 Oct 1;133(7):1578-88. PubMed PMID: 23536473.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Necrosis in DU145 prostate cancer spheroids induces COX-2/mPGES-1-derived PGE2 to promote tumor growth and to inhibit T cell activation. AU - Sha,Weixiao, AU - Olesch,Catherine, AU - Hanaka,Hiromi, AU - Rådmark,Olof, AU - Weigert,Andreas, AU - Brüne,Bernhard, Y1 - 2013/04/22/ PY - 2012/10/09/received PY - 2013/03/12/accepted PY - 2013/3/29/entrez PY - 2013/3/29/pubmed PY - 2013/9/24/medline KW - COX-2 KW - MCTS KW - PGE2 KW - cancer KW - mPGES-1 KW - necrosis KW - tumor spheroid SP - 1578 EP - 88 JF - International journal of cancer JO - Int. J. Cancer VL - 133 IS - 7 N2 - 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. SN - 1097-0215 UR - https://www.unboundmedicine.com/medline/citation/23536473/Necrosis_in_DU145_prostate_cancer_spheroids_induces_COX_2/mPGES_1_derived_PGE2_to_promote_tumor_growth_and_to_inhibit_T_cell_activation_ L2 - https://doi.org/10.1002/ijc.28181 DB - PRIME DP - Unbound Medicine ER -