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Basic Science
Dkk-3 Induces Apoptosis Through Mitochondrial and Fas Death Receptor Pathways in Human Mucinous Ovarian Cancer Cells
  1. Aiko Takata, MS*,
  2. Masakazu Terauchi, MD, PhD†,
  3. Shiro Hiramitsu, MD, PhD*,
  4. Masaya Uno, MD, PhD*,†,
  5. Kimio Wakana, MD, PhD* and
  6. Toshiro Kubota, MD, PhD*
  1. *Departments of Comprehensive Reproductive Medicine, and
  2. †Departments of Women’Departments of s Health, Tokyo Medical and Dental University; and
  3. ‡Departments of Department of Gynecology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
  1. Address correspondence and reprint requests to Masakazu Terauchi, MD, PhD, Department of Women’s Health, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo, Tokyo 113–8510, Japan. E-mail: teragyne@tmd.ac.jp.

Abstract

Objective Dkk-3 is a Wnt signaling inhibitor that is frequently inactivated in human cancers. Dkk-3 possesses an antiproliferative activity and induces apoptosis in tumor cells, suggesting that it functions as a tumor suppressor. In this study, we investigated the molecular function of Dkk-3 in human ovarian cancer cells.

Methods We assessed the levels of Dkk-3 protein expression in human mucinous and clear cell ovarian cancer cells, and compared cell viabilities between cell lines that expressed Dkk-3 and those that did not, as well as between cells that expressed Dkk-3 and those whose expression of Dkk-3 was reduced by small interfering RNA. We also evaluated the characteristic fragmentation of DNA to detect apoptosis in Dkk-3–deficient cells. To further investigate the molecular mechanisms of apoptosis, we assessed the expression of molecules involved in apoptosis signaling pathways in Dkk-3–deficient cells.

Results The expression of the Dkk-3 protein was observed in most of the ovarian cancer cell lines tested. Dkk-3–deficient cells showed faster growth than Dkk-3–replete cells. The characteristic fragmentation of DNA was not observed in Dkk-3–deficient cells, which showed decreased levels of expression in caspase-3, activated caspase-9, Bax, p53, activated caspase-8, and Fas/CD95, as well as an increase in Bcl-2 expression.

Conclusions Although Dkk-3 expression was observed in most of human ovarian cancer cell lines, Dkk-3 has a tumor-suppressive function and a proapoptotic effect, inducing apoptosis through mitochondrial and Fas death receptor pathways in human mucinous ovarian cancer MCAS cells.

  • Ovarian cancer
  • Wnt signaling
  • Caspase
  • Tumor suppressor
  • Proapoptotic

https://doi.org/10.1097/IGC.0000000000000340

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    Footnotes

    • Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.ijgc.net).

    • The authors declare no conflicts of interest.