APKCζ-dependent Repression of Yap is Necessary for Functional Restoration of Irradiated Salivary Glands with IGF-1

Overview

Journal Sci Rep

Specialty Science

Date 2018 Apr 22

PMID 29679075

Citations 23

Authors

Alejandro M Chibly

Wen Yu Wong

Maricela Pier

Hongqiang Cheng

Yongxin Mu

Ju Chen

Sourav Ghosh

Kirsten H Limesand

Affiliations

Soon will be listed here.

Abstract

Xerostomia and salivary hypofunction often result as a consequence of radiation therapy for head and neck cancers, which are diagnosed in roughly 60,000 individuals every year in the U.S. Due to the lack of effective treatments for radiation-induced salivary hypofunction, stem cell-based therapies have been suggested to regenerate the irradiated salivary glands. Pharmacologically, restoration of salivary gland function has been accomplished in mice by administering IGF-1 shortly after radiation treatment, but it is not known if salivary stem and progenitor cells play a role. We show that radiation inactivates aPKCζ and promotes nuclear redistribution of Yap in a population of label-retaining cells in the acinar compartment of the parotid gland (PG)- which comprises a heterogeneous pool of salivary progenitors. Administration of IGF-1 post-radiation maintains activation of aPKCζ and partially rescues Yap's cellular localization in label retaining cells, while restoring salivary function. Finally, IGF-1 fails to restore saliva production in mice lacking aPKCζ, demonstrating the importance of the kinase as a potential therapeutic target.

Citing Articles

Chronic Phenotypes Underlying Radiation-Induced Salivary Gland Dysfunction.

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Parotid glands have a dysregulated immune response following radiation therapy.

Gunning J, Gilman K, Zuniga T, Simpson R, Limesand K PLoS One. 2024; 19(3):e0297387.

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Radiation-induced changes in energy metabolism result in mitochondrial dysfunction in salivary glands.

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Metabolomics analysis of pathways underlying radiation-induced salivary gland dysfunction stages.

Buss L, De Oliveira Pessoa D, Snider J, Padi M, Martinez J, Limesand K PLoS One. 2023; 18(11):e0294355.

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References

Chae H, Kim D, Kim H . Growth hormone treatment and risk of malignancy. Korean J Pediatr. 2015; 58(2):41-6. PMC: 4357770. DOI: 10.3345/kjp.2015.58.2.41. View

Hirai T, Chida K . Protein kinase Czeta (PKCzeta): activation mechanisms and cellular functions. J Biochem. 2003; 133(1):1-7. DOI: 10.1093/jb/mvg017. View

Blanpain C, Fuchs E . Stem cell plasticity. Plasticity of epithelial stem cells in tissue regeneration. Science. 2014; 344(6189):1242281. PMC: 4523269. DOI: 10.1126/science.1242281. View

Grundmann O, Fillinger J, Victory K, Burd R, Limesand K . Restoration of radiation therapy-induced salivary gland dysfunction in mice by post therapy IGF-1 administration. BMC Cancer. 2010; 10:417. PMC: 3087323. DOI: 10.1186/1471-2407-10-417. View

Knox S, Lombaert I, Haddox C, Abrams S, Cotrim A, Wilson A . Parasympathetic stimulation improves epithelial organ regeneration. Nat Commun. 2013; 4:1494. PMC: 3582394. DOI: 10.1038/ncomms2493. View

Marmary Y, Adar R, Gaska S, Wygoda A, Maly A, Cohen J . Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation. Cancer Res. 2016; 76(5):1170-80. DOI: 10.1158/0008-5472.CAN-15-1671. View

Aure M, Konieczny S, Ovitt C . Salivary gland homeostasis is maintained through acinar cell self-duplication. Dev Cell. 2015; 33(2):231-7. PMC: 4406828. DOI: 10.1016/j.devcel.2015.02.013. View

Henrique D, Schweisguth F . Cell polarity: the ups and downs of the Par6/aPKC complex. Curr Opin Genet Dev. 2003; 13(4):341-50. DOI: 10.1016/s0959-437x(03)00077-7. View

Varelas X . The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease. Development. 2014; 141(8):1614-26. DOI: 10.1242/dev.102376. View

10.

Chen L, Egan L, Li Z, Greten F, Kagnoff M, Karin M . The two faces of IKK and NF-kappaB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nat Med. 2003; 9(5):575-81. DOI: 10.1038/nm849. View

11.

Murdoch-Kinch C, Kim H, Vineberg K, Ship J, Eisbruch A . Dose-effect relationships for the submandibular salivary glands and implications for their sparing by intensity modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2008; 72(2):373-82. PMC: 3734803. DOI: 10.1016/j.ijrobp.2007.12.033. View

12.

Goulas S, Conder R, Knoblich J . The Par complex and integrins direct asymmetric cell division in adult intestinal stem cells. Cell Stem Cell. 2012; 11(4):529-40. PMC: 3465556. DOI: 10.1016/j.stem.2012.06.017. View

13.

Ogawa M, Oshima M, Imamura A, Sekine Y, Ishida K, Yamashita K . Functional salivary gland regeneration by transplantation of a bioengineered organ germ. Nat Commun. 2013; 4:2498. PMC: 3806330. DOI: 10.1038/ncomms3498. View

14.

Delporte C, OConnell B, He X, Lancaster H, OConnell A, Agre P . Increased fluid secretion after adenoviral-mediated transfer of the aquaporin-1 cDNA to irradiated rat salivary glands. Proc Natl Acad Sci U S A. 1997; 94(7):3268-73. PMC: 20358. DOI: 10.1073/pnas.94.7.3268. View

15.

Man Y, Ball W, Marchetti L, Hand A . Contributions of intercalated duct cells to the normal parenchyma of submandibular glands of adult rats. Anat Rec. 2001; 263(2):202-14. DOI: 10.1002/ar.1098. View

16.

Warner S, Yashiro H, Longmore G . The Cdc42/Par6/aPKC polarity complex regulates apoptosis-induced compensatory proliferation in epithelia. Curr Biol. 2010; 20(8):677-86. PMC: 2910247. DOI: 10.1016/j.cub.2010.03.025. View

17.

Vorhagen S, Niessen C . Mammalian aPKC/Par polarity complex mediated regulation of epithelial division orientation and cell fate. Exp Cell Res. 2014; 328(2):296-302. DOI: 10.1016/j.yexcr.2014.08.008. View

18.

Yoo C, Vines J, Alexander G, Murdock K, Hwang P, Jun H . Adult stem cells and tissue engineering strategies for salivary gland regeneration: a review. Biomater Res. 2015; 18:9. PMC: 4549133. DOI: 10.1186/2055-7124-18-9. View

19.

Kwak M, Ghazizadeh S . Analysis of histone H2BGFP retention in mouse submandibular gland reveals actively dividing stem cell populations. Stem Cells Dev. 2014; 24(5):565-74. PMC: 4333511. DOI: 10.1089/scd.2014.0355. View

20.

Bralic M, Muhvic-Urek M, Stemberga V, Golemac M, Jurkovic S, Borcic J . Cell death and cell proliferation in mouse submandibular gland during early post-irradiation phase. Acta Med Okayama. 2005; 59(4):153-9. DOI: 10.18926/AMO/31948. View