Interference of Ca2+ with the proliferation of SCCOHT-1 and ovarian adenocarcinoma cells

Otte,Anna; Rauprich,Finn; von der Ohe,Juliane; Hillemanns,Peter; Hass,Ralf

doi:10.3892/ijo.2014.2518

Interference of Ca2+ with the proliferation of SCCOHT-1 and ovarian adenocarcinoma cells

Authors:
- Anna Otte
- Finn Rauprich
- Juliane von der Ohe
- Peter Hillemanns
- Ralf Hass
View Affiliations

Affiliations: Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany
Published online on: June 24, 2014 https://doi.org/10.3892/ijo.2014.2518
Pages: 1151-1158

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

A recently established cellular model for the rare small cell carcinoma of the ovary hypercalcemic type (SCCOHT-1) was characterized in comparison to ovarian adenocarcinoma cells (NIH:OVCAR-3 and SK-OV-3). The different cancer populations exhibited a common sensitivity in acidic pH milieu and a continuous proliferation in alkaline medium of pH 8.0-9.0. In the presence of elevated Ca2+ concentrations, the ovarian cancer cells demonstrated a progressively reduced proliferation within 72 h in contrast to other tumor types such as breast cancer cells. This significant growth inhibition was calcium-specific since the proliferation was unaffected after culture of the ovarian cancer cells in the presence of similar concentrations of other cations. The Ca2+ effects on the ovarian cancer cells were associated with marked differences in the activation of intracellular signaling pathways including enhanced phosphorylation of the p42/44 MAP kinase (Thr202/Tyr204). Further analysis of the signaling pathway revealed a significantly enhanced Ca2+-dependent and p42/44 MAP kinase activation-mediated prostaglandin E2 (PGE2) production in SK-OV-3 and SCCOHT-1 and to a lesser extent in NIH:OVCAR-3 cells. Vice versa, exogenous PGE2 did not affect the proliferative capacity of the ovarian cancer cells and inhibition of the Ca2+-mediated MAP kinase activation did not abolish the Ca2+-mediated cytotoxicity. Collectively, these data suggest that multiple pathways are activated by exogenous Ca2+ in the different ovarian cancer cells, including a specific MAP kinase signaling cascade with subsequent PGE2 production and a parallel pathway for the induction of cell death.

View Figures

View References

1	Otte A, Gohring G, Steinemann D, et al: A tumor-derived population (SCCOHT-1) as cellular model for a small cell ovarian carcinoma of the hypercalcemic type. Int J Oncol. 41:765–775. 2012.
2	Dickersin GR, Kline IW and Scully RE: Small cell carcinoma of the ovary with hypercalcemia: a report of eleven cases. Cancer. 49:188–197. 1982. View Article : Google Scholar : PubMed/NCBI
3	Young RH, Oliva E and Scully RE: Small cell carcinoma of the hypercalcemic type in the ovary. Gynecol Oncol. 57:7–8. 1995.PubMed/NCBI
4	Jelinic P, Mueller JJ, Olvera N, et al: Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat Genet. 46:424–426. 2014. View Article : Google Scholar : PubMed/NCBI
5	Witkowski L, Carrot-Zhang J, Albrecht S, et al: Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet. 46:438–443. 2014. View Article : Google Scholar : PubMed/NCBI
6	Ramos P, Karnezis AN, Craig DW, et al: Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat Genet. 46:427–429. 2014. View Article : Google Scholar : PubMed/NCBI
7	Scully RE: Atlas of Tumor Pathology: Tumors of the Ovary and Maldeveloped Gonads. Armed Forces Institute of Pathology; Washington, DC: 1979
8	Ulbright TM, Roth LM, Stehman FB, Talerman A and Senekjian EK: Poorly differentiated (small cell) carcinoma of the ovary in young women: evidence supporting a germ cell origin. Hum Pathol. 18:175–184. 1987. View Article : Google Scholar : PubMed/NCBI
9	Aguirre P, Thor AD and Scully RE: Ovarian small cell carcinoma. Histogenetic considerations based on immunohistochemical and other findings. Am J Clin Pathol. 92:140–149. 1989.PubMed/NCBI
10	Walt H, Hornung R, Fink D, et al: Hypercalcemic-type of small cell carcinoma of the ovary: characterization of a new tumor line. Anticancer Res. 21:3253–3259. 2001.PubMed/NCBI
11	McCluggage WG, Oliva E, Connolly LE, McBride HA and Young RH: An immunohistochemical analysis of ovarian small cell carcinoma of hypercalcemic type. Int J Gynecol Pathol. 23:330–336. 2004. View Article : Google Scholar : PubMed/NCBI
12	Harrison ML, Hoskins P, du Bois A, et al: Small cell of the ovary, hypercalcemic type - analysis of combined experience and recommendation for management. A GCIG study. Gynecol Oncol. 100:233–238. 2006. View Article : Google Scholar : PubMed/NCBI
13	Shrimali RK, Correa PD and Reed NS: Dose-dense and dose-intense chemotherapy for small cell ovarian cancer: 2 cases and review of literature. Med Oncol. 28:766–770. 2011. View Article : Google Scholar : PubMed/NCBI
14	Benrubi GI, Pitel P and Lammert N: Small cell carcinoma of the ovary with hypercalcemia responsive to sequencing chemotherapy. South Med J. 86:247–248. 1993. View Article : Google Scholar : PubMed/NCBI
15	Reed WC: Small cell carcinoma of the ovary with hypercalcemia: report of a case of survival without recurrence 5 years after surgery and chemotherapy. Gynecol Oncol. 56:452–455. 1995.PubMed/NCBI
16	Dykgraaf RH, de Jong D, van Veen M, Ewing-Graham PC, Helmerhorst TJ and van der Burg ME: Clinical management of ovarian small-cell carcinoma of the hypercalcemic type: a proposal for conservative surgery in an advanced stage of disease. Int J Gynecol Cancer. 19:348–353. 2009. View Article : Google Scholar : PubMed/NCBI
17	Barondeau J, Rodgers M, Braun L, Azarow K, Forouhar M and Faucette K: Small cell ovarian carcinoma: a rare, aggressive tumor masquerading as constipation in a teenager with a fatal outcome. J Pediatr Hematol Oncol. 32:e139–e141. 2010. View Article : Google Scholar
18	Mandel K, Yang Y, Schambach A, Glage S, Otte A and Hass R: Mesenchymal stem cells directly interact with breast cancer cells and promote tumor cell growth in vitro and in vivo. Stem Cells Dev. 22:3114–3127. 2013. View Article : Google Scholar : PubMed/NCBI
19	Bertram C and Hass R: Cellular senescence of human mammary epithelial cells (HMEC) is associated with an altered MMP-7/HB-EGF signaling and increased formation of elastin-like structures. Mech Ageing Dev. 130:657–669. 2009. View Article : Google Scholar
20	Putney JW: Capacitative calcium entry: from concept to molecules. Immunol Rev. 231:10–22. 2009. View Article : Google Scholar : PubMed/NCBI
21	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
22	Schwartz GG and Skinner HG: Prospective studies of total and ionized serum calcium in relation to incident and fatal ovarian cancer. Gynecol Oncol. 129:169–172. 2013. View Article : Google Scholar : PubMed/NCBI
23	Trump BF and Berezesky IK: Calcium-mediated cell injury and cell death. FASEB J. 9:219–228. 1995.PubMed/NCBI
24	Nomura M, Ueno A, Saga K, Fukuzawa M and Kaneda Y: Accumulation of cytosolic calcium induces necroptotic cell death in human neuroblastoma. Cancer Res. 74:1056–1066. 2014. View Article : Google Scholar : PubMed/NCBI
25	Ungefroren H, Sebens S, Seidl D, Lehnert H and Hass R: Interaction of tumor cells with the microenvironment. Cell Commun Signal. 9:182011. View Article : Google Scholar : PubMed/NCBI
26	Hass R and Otte A: Mesenchymal stem cells as all-round supporters in a normal and neoplastic microenvironment. Cell Commun Signal. 10:262012. View Article : Google Scholar : PubMed/NCBI
27	Van Rossum GS, Klooster R, van den Bosch H, Verkleij AJ and Boonstra J: Phosphorylation of p42/44(MAPK) by various signal transduction pathways activates cytosolic phospholipase A(2) to variable degrees. J Biol Chem. 276:28976–28983. 2001.
28	Koehler L, Hass R, DeWitt DL, Resch K and Goppelt-Struebe M: Glucocorticoid-induced reduction of prostanoid synthesis in TPA-differentiated U937 cells is mainly due to a reduced cyclooxygenase activity. Biochem Pharmacol. 40:1307–1316. 1990. View Article : Google Scholar
29	Rehfeldt W, Hass R and Goppelt-Struebe M: Characterization of phospholipase A2 in monocytic cell lines. Functional and biochemical aspects of membrane association. Biochem J. 276:631–636. 1991.PubMed/NCBI
30	Rask K, Zhu Y, Wang W, Hedin L and Sundfeldt K: Ovarian epithelial cancer: a role for PGE2-synthesis and signalling in malignant transformation and progression. Mol Cancer. 5:622006. View Article : Google Scholar : PubMed/NCBI
31	Medeiros A, Peres-Buzalaf C, Fortino Verdan F and Serezani CH: Prostaglandin E2 and the suppression of phagocyte innate immune responses in different organs. Mediators Inflamm. 2012:3275682012. View Article : Google Scholar : PubMed/NCBI