Background: Mitochondrial dynamics is involved in the regulation of apoptosis. Results: p53 regulates mitochondrial dynamics by interacting with Prohibitin 1 and subsequent releasing Opa1 for Oma1-mediated processing, thereby promoting apoptosis and chemoresponsiveness. Conclusion: CDDP resistance is in part due to dysregulation of p53-induced, Oma1-mediated L-Opa1 processing and mitochondrial fragmentation. Significance: Understanding the regulation of mitochondrial dynamics may offer new strategies for overcoming chemoresistance.

Polycystic ovarian syndrome (PCOS) is a heterogeneous syndrome associated with follicle growth arrest, minimal granulosa cell proliferation, dysregulated sex hormone profile, hyperthecosis, and insulin resistance. Using a 5α-dihydrotestosterone (DHT)-induced rat model that recapitulates the reproductive and metabolic phenotypes of human PCOS, we have examined the steroidogenic capability of granulosa cells from DHT-treated rats. Gene expression of several key steroidogenic enzymes including p450 side-chain cleavage enzyme (p450scc), aromatase, steroidogenic acute regulatory protein, hydroxysteroid dehydrogenase-17β, and hydroxysteroid dehydrogenase-3β were markedly lower in DHT-treated rats than the controls, although the responsiveness of their granulosa cells to FSH was higher. Expression of the adipokine chemerin and its receptor, chemokine receptor-like 1, was evident in control and DHT-treated rats, with significantly higher ovarian mRNA abundances and protein contents of chemerin and its receptor. Recombinant chemerin decreases basal estradiol secretion in granulosa cells from DHT-treated rats. When the inhibitory role of chemerin on steroidogenesis was further examined in vitro, chemerin suppressed FSH-induced progesterone and estradiol secretion in cultured preantral follicles and granulosa cells. Chemerin also inhibits FSH-induced aromatase and p450scc expression in granulosa cells. Overexpression of nuclear receptors NR5a1 and NR5a2 promotes p450scc and aromatase expression, respectively, which is suppressed by chemerin. These findings suggest that chemerin is a novel negative regulator of FSH-induced follicular steroidogenesis and may contribute to the pathogenesis of PCOS.

No abstract

In the present study, we have investigated the cellular mechanisms of androgen-induced antral follicular growth arrest and the possible involvement of chemerin and its receptor chemokine-like receptor 1 (CMKLR1) in this process, using a chronically androgenized rat model. We hypothesize that hyperandrogenism induces antral follicle growth arrest via the action of chemerin and ovarian structural changes, resulting from granulosa cell and oocyte apoptosis and theca cell survival. Dihydrotestosterone (DHT) treatment resulted in increased expression of chemerin and CMKLR1 in antral follicles, absence of corpus luteum, and increased atypical follicles. Addition of chemerin to follicle cultures induced granulosa cell apoptosis and suppressed basal, FSH- and growth differentiation factor-9-stimulated follicular growth. DHT down-regulated aromatase expression and increased active caspase-3 content and DNA fragmentation in granulosa cells in vivo. These changes were accompanied by higher phosphatase and tensin homolog and lower phospho-Akt (Ser473) content in antral follicles and higher calpain expression and down-regulation of cytoskeletal proteins in atypical follicles, which were constituted predominantly of theca cells. DHT also activated granulosa cell caspase-3, decreased X-linked inhibitor of apoptosis protein, poly(ADP-ribose) polymerase, and phospho-Akt contents and induced apoptosis in vitro, responses readily attenuated by forced X-linked inhibitor of apoptosis protein expression. These findings are consistent with our hypothesis that antral follicular growth arrest in DHT-treated rats results from increased chemerin expression and action, as well as changes in follicular cell fate and structure, which are a consequence of dysregulated interactions of pro-survival and pro-apoptotic modulators in a cell-specific manner. Our observations suggest that this chronically androgenized rat model may be useful for studies on the long-term effects of androgens on folliculogenesis and may have implications for the female reproductive disorders associated with hyperandrogenism.

Background: PARC sequesters p53 in the cytoplasm; dysregulation of p53 localization/function contributes to chemoresistance in OVCA. Results: Cisplatin promotes calpain-mediated PARC down-regulation, mitochondrial and nuclear p53 accumulation, and apoptosis in chemosensitive but not resistant OVCA cells. Conclusion: Dysregulation of calpain-mediated PARC processing promotes chemoresistance in OVCA cells. Significance: PARC down-regulation represents a novel strategy to prevent/reverse resistance to cisplatin-based chemotherapy.

Choriocarcinoma is one of the gestational trophoblastic neoplasias (GTNs) that originate in the chorionic villi and the extravillous trophoblast. Long noncoding RNAs (lncRNAs) are a type of non-protein-coding RNAs that have recently been implicated in human tumorigenesis. The present study investigated the role of the lncRNA LINC00261 in cell proliferation, metastasis, and apoptosis in choriocarcinoma cell lines. The transcription level of LINC00261 was significantly lower in choriocarcinoma tissues and in choriocarcinoma cell lines. Overexpression of LINC00261 caused a decrease in cell proliferation and arrested the cell cycle at the G0/G1 phase. Furthermore, overexpression of LINC00261 inhibited cell migration and invasion. Meanwhile, it promoted cell apoptosis and the relative activities of caspase 3 and caspase 9 in choriocarcinoma JEG-3 and JAR cells. These data suggested that LINC00261 promotes cell proliferation and metastasis in choriocarcinoma. Our data might provide novel insight into the early diagnosis and treatment of choriocarcinoma in clinics.

Our data suggest that vorinostat is active in RRCL with a known defective apoptotic machinery, it can active alternative cell death pathways. Given the multiple pathways affected by HDAC inhibition, vorinostat can potentially be used to overcome acquired resistant to chemotherapy in aggressive B cell lymphoma.

In order to identify cellular pathways associated with therapy-resistant aggressive lymphoma, we generated rituximab-resistant cell lines (RRCL) and found that the acquirement of rituximab resistance was associated with a deregulation in glucose metabolism and an increase in the apoptotic threshold leading to chemotherapy resistance. Hexokinase II (HKII), the predominant isoform overexpressed in cancer cells, has dual functions of promoting glycolysis as well as inhibiting mitochondrialmediated apoptosis. We found that RRCL demonstrated higher HKII levels. Targeting HKII resulted in decreased mitochondrial membrane potential, ATP production, cell viability; and re-sensitization to chemotherapy agents. Analyzed gene expression profiling data from diffuse large B-cell lymphoma patients, high-HKII levels were associated with a shorter progression free survival (PFS) and/or overall survival (OS). Our data suggest that over-expression of HKII is associated with resistance to rituximab and chemotherapy agents in aggressive lymphoma and identifies this enzyme isoform as a potential therapeutic target. www.impactjournals.com/oncotarget/