ReviewCancer/Testis Antigens into mitochondria: a hub between spermatogenesis, tumorigenesis and mitochondrial physiology adaptation
Section snippets
Introduction – Discovering CTAs
Cancer/Testis Antigens (CTAs) represent a group of proteins whose expression under physiological conditions is restricted to testis, but also activated in many human cancers. The first CTA, MZ2-E, named MAGE-A1, was identified in 1991 as a melanoma tumor antigen, recognized by cytotoxic T lymphocytes in vitro (van der Bruggen et al., 1991). Later, the screening of a recombinant cDNA expression library, built from sera of Melanoma patients, unraveled a new family of antigens sharing two features
CTAs expression during cancer
CTAs expression can be specific to a single tumorigenesis step or common to all steps of cancer development, leading to three expression profiles. First, most CTAs are broadly expressed during metastasis, while less frequently in primary tumors. For example, MAGE-A1 expression is observed in 51% of distant metastasis, but only in 20% of melanoma primary tumors. Similarly, MAGE-A4 is expressed in 44% of metastatic malignant melanoma, but only in 9% of primary tumors (Barrow, 2006). These
CTAs expression during spermatogenesis
Spermatogenesis occurs in testis in seminiferous tubules, to produce mature functional spermatozoa (Neto et al., 2016). The seminiferous tubule is composed of somatic cells and Sertoli cells supporting the development of the germline cells: spermatogonia, spermatocytes, spermatids and spermatozoa (Fig. 1). Spermatogonia germ cells, which are located at the periphery of the seminiferous tubules, are in contact with blood. They proliferate and differentiate into primary spermatocytes by mitotic
Shared features between spermatogenesis and cancer: energy metabolism sustains cell proliferation
The very unique expression pattern of CTAs suggests their involvement in common mechanisms between spermatogenesis and tumorigenesis. Beyond the processes involved in cell proliferation, immortalization, invasion, and migration (see reviews by (Simpson et al., 2005, Whitehurst, 2014)), we wish to raise here the fact that spermatogenesis and tumorigenesis similarly involve a major metabolic shift, likely involving major mitochondrial regulations. Indeed, during carcinogenesis, cancer cells
Prediction of CTAs acting on mitochondria
To identify and predict if some CTAs interfere with mitochondrial physiology, we used two in silico approaches. The first one identified all the CTAs that are already described in bibliographic databases as impacting on mitochondrial functions. The second, predicted all CTAs protein sequences that included a mitochondria targeting sequence (MTS), underlying their potential mitochondrial localization.
CTAs functions into mitochondria
With the first approach based on bibliographical data mining, we identified 5 CTAs acting on mitochondria: SPATA19, GPAT2, FATE1, COX6B2 and KIAA0100.
SPATA19 (Spermatogenesis Associated 19) is a small mitochondrial protein of 154 amino acids (aa), with a 20 aa MTS. During spermatogenesis, SPATA19 is expressed in round spermatids and in the midpiece of the sperm tail. Study of a germ cell-specific Spata19 KO mouse revealed that this protein is required for appropriate flagellum formation and
Discussion and open questions
In summary, with our two approaches, we identified 70 mitoCTAs among the 276 known CTAs: 67 CTAs predicted to harbor a MTS and 3 without a MTS. Their expression might be related to specific mitochondrial functions involved in spermatogenesis in physiological condition, and in tumorigenesis in a pathological condition. Initially, our hypothesis concerning the possible role of CTAs in mitochondria was based on the fact that both spermatogenesis and tumorigenesis involved a common major metabolic
CRediT authorship contribution statement
Jade Aurrière: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing - original draft, Writing - review & editing. David Goudenège: Data curation, Formal analysis, Investigation, Methodology, Resources, Software. Olivier R. Baris: Writing - review & editing. Magalie Boguenet: Data curation, Investigation, Writing - review & editing. Pascale May-Panloup: Writing - review & editing. Guy Lenaers: Conceptualization,
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We acknowledge Dr. Layon for promoting scientific discussions and Sheena M Aris, Shar-Yin N Huang and Brunilde M. Gril for the critical reading of the manuscript.
Funding
This work was supported by the Université d’Angers, CHU d’Angers, the Région Pays de la Loire and Angers Loire Métropole.
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2022, MitochondrionCitation Excerpt :Also, FATE1 inhibits a pro-apoptotic pathway, by preventing BIK (BCL2-Interacting Killer) accumulation to promoting cell survival (Maxfield, 2015). Additionally to these CTAs, we recently reported 143 transcripts encoded by 67 CTAs genes, with a potential mitochondrial targeting sequence (MTS), that we called mitoCTAs (Aurrière et al., 2021). The vast majority of these mitoCTAs have almost no known function in mitochondria.
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