Selenoprotein K deficiency inhibits melanoma by reducing calcium flux required for tumor growth and metastasis
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Michael P. Marciel1, Vedbar S. Khadka2, Youping Deng2, Pascal Kilicaslan3, Andrew Pham1, Pietro Bertino1, Katie Lee1, Suzie Chen4, Natalija Glibetic5, FuKun W. Hoffmann1, Michelle L. Matter5 and Peter R. Hoffmann1
1Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, U.S.A.
2Bioinformatics Core in the Department of Complementary and Integrative Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, U.S.A.
3Biotechnology Department, University of Applied Sciences Mannheim, Mannheim, Germany
4Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey, U.S.A.
5The University of Hawaii Cancer Center, Honolulu, Hawaii, U.S.A.
Peter R. Hoffmann, email: email@example.com
Keywords: selenium; migration; inositol 1,4,5-triphosphate receptor; calcium channel; palmitoylation
Received: October 07, 2017 Accepted: January 23, 2018 Published: February 03, 2018
Interest has emerged in the therapeutic potential of inhibiting store operated calcium (Ca2+) entry (SOCE) for melanoma and other cancers because malignant cells exhibit a strong dependence on Ca2+ flux for disease progression. We investigated the effects of deleting Selenoprotein K (SELENOK) in melanoma since previous work in immune cells showed SELENOK was required for efficient Ca2+ flux through the endoplasmic reticulum Ca2+ channel protein, inositol 1,4,5-trisphosphate receptor (IP3R), which is due to the role SELENOK plays in palmitoylating and stabilizing the expression of IP3R. CRISPR/Cas9 was used to generate SELENOK-deficiency in human melanoma cells and this led to reduced Ca2+ flux and impaired IP3R function, which inhibited cell proliferation, invasion, and migration. Ca2+-dependent signaling through calcineurin was inhibited with SELENOK-deficiency, and gene array analyses together with evaluation of transcript and protein levels showed altered transcriptional programs that ultimately disrupted stemness and pro-growth properties. In vivo investigations were conducted using the Grm1-Tg transgenic mouse strain that develops spontaneous metastatic melanoma, which was crossed with SELENOK−/− mice to generate the following littermates: Grm1-Tg/SELENOK−/−, Grm1-Tg/SELENOK−/+, Grm1-Tg/SELENOK+/+. SELENOK-deficiency in Grm1-Tg/SELENOK−/− male and female mice inhibited primary tumor growth on tails and ears and reduced metastasis to draining lymph nodes down to levels equivalent to non-tumor control mice. Cancer stem cell pools were also decreased in Grm1-Tg/SELENOK−/− mice compared to littermates. These results suggest that melanoma requires SELENOK expression for IP3R dependent maintenance of stemness, tumor growth and metastasic potential, thus revealing a new potential therapeutic target for treating melanoma and possibly other cancers.
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