MEIKIN expression and its C-terminal phosphorylation by PLK1 is closely related the metaphase-anaphase transition by affecting cyclin B1 and Securin stabilization in meiotic oocyte.

Oocyte meiotic maturation failure and chromosome abnormality is one of the main causes of infertility, abortion, and diseases. The mono-orientation of sister chromatids during the first meiosis is important for ensuring accurate chromosome segregation in oocytes. MEIKIN is a germ cell-specific protein that can regulate the mono-orientation of sister chromatids and the protection of the centromeric cohesin complex during meiosis I. Here we found that MEIKIN is a maternal protein that was highly expressed in mouse oocytes before the metaphase I (MI) stage, but became degraded by the MII stage and dramatically reduced after fertilization. Strikingly, MEIKIN underwent phosphorylation modification after germinal vesicle breakdown (GVBD), indicating its possible function in subsequent cellular event regulation. We further showed that MEIKIN phosphorylation was mediated by PLK1 at its carboxyl terminal region and its C-terminus was its key functional domain. To clarify the biological significance of meikin degradation during later stages of oocyte maturation, exogenous expression of MEIKIN was employed, which showed that suppression of MEIKIN degradation resulted in chromosome misalignment, cyclin B1 and Securin degradation failure, and MI arrest through a spindle assembly checkpoint (SAC)-independent mechanism. Exogenous expression of MEIKIN also inhibited metaphase II (MII) exit and early embryo development. These results indicate that proper MEIKIN expression level and its C-terminal phosphorylation by PLK1 are critical for regulating the metaphase-anaphase transition in meiotic oocyte. The findings of this study are important for understanding the regulation of chromosome segregation and the prevention meiotic abnormality.

The Impact of Mitochondria in Ovarian Cancer Cell Metabolism, Proliferation, and Metastasis.

Mitochondrial dysfunctions are significantly implicated in cancer initiation, progression, and metastasis, which have been shown for several cancers including ovarian cancer.An increase in mitochondrial dysfunction is also associated with drug resistance along with cancer progression, which in part is related to its specific microenvironment that is characterized by ascites, low glucose levels, and hypoxia that causes ovarian cancer cells to switch to mitochondrial respiration to enable their survival. Peritoneal ascitic fluid accumulation is a specific feature of ovarian cancer, and it is a major cause of its metastatic spread that also presents challenges for effective treatment. Among the treatment difficulties for ovarian cancer is the mutation rate and frequency of mtDNA in ovarian cancer tissue that can affect the efficiency of chemotherapeutic drugs. The varied and multiple mutations of different types enable metabolic reprogramming, cancer cell proliferation, and drug resistance.New specific information on mechanisms underlying several of the mitochondrial dysfunctions has led to proposing various mitochondrial determinants as targets for ovarian cancer therapy, which include targeting specific mitochondrial proteins and phosphoproteins as well as reactive oxygen species (ROS) that accumulate abnormally in cancer cells. Because of the genetically and histologically heterogeneous nature of the disease, combination therapy approaches will be necessary to combat the disease and achieve progress in effective treatment of ovarian cancer. This chapter will address (1) mitochondrial vulnerabilities underlying dysfunction and disease; (2) mitochondrial dysfunction in ovarian cancer; (3) present treatment difficulties for ovarian cancer and new potential treatment strategies to target ovarian cancer mitochondrial metabolism; and (4) biobehavioral factors influencing ovarian cancer development.

The Impact of Centrosome Pathologies on Ovarian Cancer Development and Progression with a Focus on Centrosomes as Therapeutic Target.

The impact of centrosome abnormalities on cancer cell proliferation has been recognized as early as 1914 (Boveri, Zur Frage der Entstehung maligner Tumoren. Jena: G. Fisher, 1914), but vigorous research on molecular levels has only recently started when it became fully apparent that centrosomes can be targeted for new cancer therapies. While best known for their microtubule-organizing capabilities as MTOC (microtubule organizing center) in interphase and mitosis, centrosomes are now further well known for a variety of different functions, some of which are related to microtubule organization and consequential activities such as cell division, migration, maintenance of cell shape, and vesicle transport powered by motor proteins, while other functions include essential roles in cell cycle regulation, metabolic activities, signal transduction, proteolytic activity, and several others that are now heavily being investigated for their role in diseases and disorders (reviewed in Schatten and Sun, Histochem Cell Biol 150:303-325, 2018; Schatten, Adv Anat Embryol Cell Biol 235:43-50, 2022a; Schatten, Adv Anat Embryol Cell Biol 235:17-35, 2022b).Cancer cell centrosomes differ from centrosomes in noncancer cells in displaying specific abnormalities that include phosphorylation abnormalities, overexpression of specific centrosomal proteins, abnormalities in centriole and centrosome duplication, formation of multipolar spindles that play a role in aneuploidy and genomic instability, and several others that are highlighted in the present review on ovarian cancer. Ovarian cancer cell centrosomes, like those in other cancers, display complex abnormalities that in part are based on the heterogeneity of cells in the cancer tissues resulting from different etiologies of individual cancer cells that will be discussed in more detail in this chapter.Because of the critical role of centrosomes in cancer cell proliferation, several lines of research are being pursued to target centrosomes for therapeutic intervention to inhibit abnormal cancer cell proliferation and control tumor progression. Specific centrosome abnormalities observed in ovarian cancer will be addressed in this chapter with a focus on targeting such aberrations for ovarian cancer-specific therapies.