bims-glecem 2022-02-06 papers

bims-glecem

Biomed News

on Glycogen metabolism in exercise, cancer and energy metabolism

Issue of 2022‒02‒06
thirteen papers selected by
Dipsikha Biswas, Københavns Universitet

Minimum Effective Dose to Achieve Biochemical Correction With AAV Vector-Mediated Gene Therapy in Mice With Pompe Disease.
Aerobic capacity and skeletal muscle characteristics in glycogen storage disease IIIa: an observational study.
A glucose-based molecular rotor inhibitor of glycogen phosphorylase as a probe of cellular enzymatic function.
GSK-3α/β Activity Negatively Regulates MMP-1/9 Expression to Suppress Mycobacterium tuberculosis Infection.
Corilagin decreases insulin resistance in polycystic ovary syndrome rat model through regulating AMPK/GSK3β pathway.
Secondary diabetes as a rare complication of glycogen storage disease 1a: case report and review of literature.
The Reduction of Tau Hyperphosphorylation by Cornel Iridoid Glycosides Is Mediated by Their Influence on Calpain Activity.
Taurine supplementation enhances endurance capacity by delaying blood glucose decline during prolonged exercise in rats.
Effect of endurance training and PGC-1α overexpression on calculated lactate production volume during exercise based on blood lactate concentration.
The GSK3 kinase and LZTR1 protein regulate the stability of Ras family proteins and the proliferation of pancreatic cancer cells.
Leucine supplementation during late gestation globally alters placental metabolism and nutrient transport via modulation of the PI3K/AKT/mTOR signaling pathway in sows.
Investigation of potential behavioral and physiological effects of caffeine on D. magna.
PNMA5 knockdown suppresses the proliferation, invasion, and metastasis of epithelial ovarian cancer cells.

Hum Gene Ther. 2022 Feb 01.

Minimum Effective Dose to Achieve Biochemical Correction With AAV Vector-Mediated Gene Therapy in Mice With Pompe Disease.

Sangoh Han, Dorothy Brooke Gheorghiu, Songtao Li, Hye Ri Kang, Dwight Koeberl.

Pompe disease is an autosomal recessive lysosomal storage disorder caused by deficiency of acid α-glucosidase (GAA), resulting in skeletal muscle weakness and cardiomyopathy. Muscle weakness progresses despite currently available therapy, which has prompted the development of gene therapy with adeno-associated virus (AAV) type 2 vectors cross-packaged as AAV8 (2/8). Preclinical studies of gene therapy demonstrated that the minimum effective dose for biochemical correction with AAV2/8-LSPhGAA was approximately 2 x 1011 vector genomes (vg)/kg body weight. The current study examined the transduction of AAV2/8-LSPeGFP vector in adult GAA-KO mice with Pompe disease, and correlated that degree of transduction with the biochemical correction achieved by the same dose of AAV2/8-LSPhGAA. The minimum effective dose was found to be approximately 2 x 1011 vg/kg, with all hepatocytes variably transducing at this dose. At this dose, liver GAA significantly increased, while liver glycogen significantly decreased. The 2 x 1011 vg/kg dose was sufficient to significantly decrease diaphragm glycogen. However, the heart, diaphragm, and quadriceps all required a four-fold higher dose to achieve correction of GAA deficiency in association with significant clearance of stored glycogen, which correlated with increased serum GAA activity. These data indicate that AAV2/8-LSPeGFP transduced all hepatocytes when the 2 x 1011 vg/kg dose was administered, which correlated with partial biochemical correction from the equivalent dose of AAV2/8-LSPhGAA. Together these data support the conclusion that substantial transduction of the liver is required to achieve biochemical correction from AAV2/8-LSPhGAA.

DOI: https://doi.org/10.1089/hum.2021.252
Orphanet J Rare Dis. 2022 Jan 31. 17(1): 28

Aerobic capacity and skeletal muscle characteristics in glycogen storage disease IIIa: an observational study.

Philip J Hennis, Elaine Murphy, Rick I Meijer, Robin H Lachmann, Radha Ramachandran, Claire Bordoli, Gurinder Rayat, David J Tomlinson.

  BACKGROUND: Individuals with glycogen storage disease IIIa (GSD IIIa) (OMIM #232400) experience muscle weakness and exercise limitation that worsen through adulthood. However, normative data for markers of physical capacity, such as strength and cardiovascular fitness, are limited. Furthermore, the impact of the disease on muscle size and quality is unstudied in weight bearing skeletal muscle, a key predictor of physical function. We aim to produce normative reference values of aerobic capacity and strength in individuals with GSD IIIa, and to investigate the role of muscle size and quality on exercise impairment.RESULTS: Peak oxygen uptake (V̇O2peak) was lower in the individuals with GSD IIIa than predicted based on demographic data (17.0 (9.0) ml/kg/min, 53 (24)% of predicted, p = 0.001). Knee extension maximum voluntary contraction (MVC) was also substantially lower than age matched predicted values (MVC: 146 (116) Nm, 57% predicted, p = 0.045), though no difference was found in MVC relative to body mass (1.88 (2.74) Nm/kg, 61% of predicted, p = 0.263). There was a strong association between aerobic capacity and maximal leg strength (r = 0.920; p = 0.003). Substantial inter-individual variation was present, with a high physical capacity group that had normal leg strength (MVC), and relatively high V̇O2peak, and a low physical capacity that display impaired strength and substantially lower V̇O2peak. The higher physical capacity sub-group were younger, had larger Vastus Lateralis (VL) muscles, greater muscle quality, undertook more physical activity (PA), and reported higher health-related quality of life.
CONCLUSIONS: V̇O2peak and knee extension strength are lower in individuals with GSD IIIa than predicted based on their demographic data. Patients with higher physical capacity have superior muscle size and structure characteristics and higher health-related quality of life, than those with lower physical capacity. This study provides normative values of these important markers of physical capacity.

Keywords:  Aerobic capacity; Glycogen storage disease type IIIa; Maximum voluntary contraction; Skeletal muscle

DOI:  https://doi.org/10.1186/s13023-022-02184-1
Org Biomol Chem. 2022 Feb 04.

A glucose-based molecular rotor inhibitor of glycogen phosphorylase as a probe of cellular enzymatic function.

Michail-Panagiotis Minadakis, Konstantinos F Mavreas, Dionysios D Neofytos, Maria Paschou, Artemis Kogkaki, Varvara Athanasiou, Michael Mamais, Daniele Veclani, Hermis Iatrou, Alessandro Venturini, Evangelia D Chrysina, Panagiota Papazafiri, Thanasis Gimisis.

Molecular rotors belong to a family of fluorescent compounds characterized as molecular switches, where a fluorescence on/off signal signifies a change in the molecule's microenvironment. Herein, the successful synthesis and detailed study of (E)-2-cyano-3-(p-(dimethylamino)phenyl)-N-(β-D-glucopyranosyl)acrylamide (RotA), is reported. RotA was found to be a strong inhibitor of rabbit muscle glycogen phosphorylase (RMGPb), that binds at the catalytic site of the enzyme. RotA's interactions with the residues lining the catalytic site of RMGPb were determined by X-ray crystallography. Spectroscopic studies coupled with theoretical calculations proved that RotA is a molecular rotor. When bound in the catalytic channel of RMGPb, it behaved as a light switch, generating a strong fluorescence signal, allowing utilization of RotA as a probe that locates glycogen phosphorylase (GP). RotA, mono-, di- and per-acetylated derivatives, as well as nanoparticles with RotA encapsulated in polyethylene glycol-poly-L-histidine, were used in live cell fluorescence microscopy imaging to test the delivery of RotA through the plasma membrane of HepG2 and A431 cells, with the nanoparticles providing the best results. Once in the intracellular milieu, RotA exhibits remarkable colocalization with GP and significant biological effects, both in cell growth and inhibition of GP.

DOI: https://doi.org/10.1039/d1ob02211c
Front Immunol. 2021 ;12 752466

GSK-3α/β Activity Negatively Regulates MMP-1/9 Expression to Suppress Mycobacterium tuberculosis Infection.

Xinying Zhou, Linmiao Lie, Yao Liang, Hui Xu, Bo Zhu, Yingqi Huang, Lijie Zhang, Zelin Zhang, Qianna Li, Qi Wang, Zhenyu Han, Yulan Huang, Honglin Liu, Shengfeng Hu, Chaoying Zhou, Qian Wen, Li Ma.

  Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection is the deadliest infectious disease and a global health problem. Macrophages (Mφs) and neutrophils that can phagocytose Mtb represent the first line of immune response to infection. Glycogen synthase kinase-3α/β (GSK-3α/β) represents a regulatory switch in host immune responses. However, the efficacy and molecular mechanisms of how GSK-3α/β interacts with Mtb infection in Mφs remain undefined. Here, we demonstrated that Mtb infection downregulated GSK-3α/β activity and promoted matrix metalloproteinase-1 (MMP-1) and MMP-9 expressions in Mφs derived from acute monocytic human leukemia THP-1 cells (THP-1-Mφs). We confirmed the upregulation of MMP-9 expression in tissues of TB patients compared with patients of chronic inflammation (CI). In THP-1-Mφs and C57BL/6 mice, GSK-3α/β inhibitor SB216763 significantly increased MMP-1/9 production and facilitated Mtb load, while MMP inhibitors blocked MMP-1/9 expression and Mtb infection. Consistently, GSK-3α/β silencing significantly increased MMP-1/9 expression and Mtb infection, while overexpression of GSK-3α/β and constitutive activated GSK-3α/β mutants significantly reduced MMP-1/9 expression and Mtb infection in THP-1-Mφs. MMP-1/9 silencing reduced Mtb infection, while overexpression of MMP-1/9 promoted Mtb infection in THP-1-Mφs. We further found that GSK-3α/β inhibition increased Mtb infection and MMP-1/9 expression was blocked by ERK1/2 inhibitor. Additionally, we showed that protein kinase C-δ (PKC-δ) and mammalian target of rapamycin (mTOR) reduced GSK-3α/β activity and promoted MMP-1/9 production in Mtb-infected THP-1-Mφs. In conclusion, this study suggests that PKC-δ-mTOR axis suppresses GSK-3α/β activation with acceleration of MMP-1/9 expression through phospho-ERK1/2. These results reveal a novel immune escape mechanism of Mtb and a novel crosstalk between these critical signaling pathways in anti-TB immunity.

Keywords:  GSK-3α/β; MMP-1; MMP-9; Mycobacteria tuberculosis; macrophages

DOI:  https://doi.org/10.3389/fimmu.2021.752466
Transl Cancer Res. 2020 May;9(5): 3242-3248

Corilagin decreases insulin resistance in polycystic ovary syndrome rat model through regulating AMPK/GSK3β pathway.

Beili Lv, Xinrong Li, Haiyan Wang.

  Background: This study aims to explore the effects of Corilagin on insulin resistance (IR) of polycystic ovary syndrome (PCOS) and the underlying mechanisms.Methods: The PCOS rat model was established by subcutaneously injected with dehydroepiandrosterone (DHEA) of 6 mg/kg/day. Body weight and ovary weight were recorded. Serum glucose and insulin concentration were analyzed with commercial kits. The expression of adenosine monophosphate-activated protein kinase (AMPK) and glycogen synthase kinase 3β (GSK3β) was detected by Western blot.
Results: The results showed that DHEA could induce ovarian dysfunction of rats and Corilagin alleviated DHEA-induced ovarian dysfunction. Corilagin reduced DHEA-induced increase of serum glucose and insulin concentration. Corilagin increased the expression level of p-AMPK/AMPK and p-GSK3β/GSK3β of rat ovarian induced by DHEA.
Conclusions: The present research reported the protective effects of Corilagin on PCOS, and demonstrated the protection effect was related to decreasing IR through regulating AMPK/GSK3β pathway.

Keywords:  Adenosine monophosphate-activated protein kinase (AMPK); Corilagin; insulin resistance (IR); polycystic ovary syndrome (PCOS)

DOI:  https://doi.org/10.21037/tcr.2020.04.27
Pediatr Endocrinol Diabetes Metab. 2021 ;pii: 45144. [Epub ahead of print]27(4): 283-286

Secondary diabetes as a rare complication of glycogen storage disease 1a: case report and review of literature.

Anshita Aggarwal, Deepika Patel, Bindu Kulshreshtha.

  Glycogen storage diseases (GSDs) are disorders of carbohydrate metabolism and hypoglycemia is their hallmark. Secondary diabetes with glycogen storage disease, which seems rather paradoxical, has been rarely reported. A 13-year-old girl previously diagnosed to have GSD 1a presented to the emergency with multiple episodes of vomiting and loss of consciousness. She had hyperglycemia, ketonuria, hyperlactatemia and metabolic acidosis, suggestive of diabetic ketosis with acidosis possibly contributed by both high serum lactate and serum ketones. Her glycated hemoglobin was high, with detectable serum insulin levels, which suggested secondary diabetes in the background of GSD Ia. Her management posed a therapeutic challenge. She was managed with insulin and achieved good glycemic control. We wish to conclude that GSD may rarely lead to secondary diabetes as a complication and the management is complex owing to the nature of the disease. Insulin remains the mainstay of the treatment.

Keywords:   diabetes; insulin.; glycogen storage disease

DOI:  https://doi.org/10.5114/pedm.2021.109121
Evid Based Complement Alternat Med. 2022 ;2022 9213046

The Reduction of Tau Hyperphosphorylation by Cornel Iridoid Glycosides Is Mediated by Their Influence on Calpain Activity.

Kaiwen Guo, Cuicui Yang, Lan Zhang.

Alzheimer's disease (AD) is the most common type of dementia, and the abnormal hyperphosphorylation of the tau protein is the main component of its pathogenesis. Calpain was found to be abnormally activated in neurofibrillary tangles (NFTs) in a previous report. Cornel iridoid glycosides (CIG) have been reported to reduce the hyperphosphorylation of tau protein. Nevertheless, the role of calpain in the reduction tau hyperphosphorylation by CIG remains unclear. In the present study, we investigated the effect of CIG on calpain activity through in vitro and in vivo experiments. Western blotting results suggested that CIG decreased the phosphorylation of tau at Ser 404 and Ser 262 sites in P301S mice. Moreover, CIG inhibited the activity of calpain and glycogen synthase kinase 3β (GSK-3β) and enhanced the activity of protein phosphatase 2A (PP2A) both in vivo and in vitro. CIG also inhibited the activation of PP2A and reduced the GSK-3β activity caused by the calpain activator dibucaine. In addition, the main components of CIG, morroniside and loganin, play an equivalent role in reducing calpain activity, as the effect of their combined use is equivalent to that of CIG. The abovementioned findings revealed that CIG improved PP2A activity and reduced GSK-3β activity by adjusting the activity of calpain 1, leading to a reduction in the phosphorylation of tau. This study highlights the remarkable therapeutic potential of CIG for managing AD.

DOI: https://doi.org/10.1155/2022/9213046
Amino Acids. 2022 Feb 05.

Taurine supplementation enhances endurance capacity by delaying blood glucose decline during prolonged exercise in rats.

Shoichi Komine, Teruo Miyazaki, Keisuke Ishikura, Takashi Matsui, Takashi Miyoshi, Song-Gyu Ra, Akira Honda, Hideaki Soya, Shumpei Miyakawa, Hajime Ohmori.

  Taurine enhances physical performance; however, the underlying mechanism remains unclear. This study examined the effect of taurine on the overtime dynamics of blood glucose concentration (BGC) during endurance exercise in rats. Male F344 rats were subjected to transient treadmill exercise until exhaustion following 3 weeks of taurine supplementation or non-supplementation (TAU and CON groups). Every 10 min during exercise, BGC was measured in blood collected through cannulation of the jugular vein. Gluconeogenesis-, lipolysis-, and fatty acid oxidation-related factors in the plasma, liver, and skeletal muscles were also analyzed after 120-min run. Exercise time to exhaustion was significantly longer with taurine supplementation. BGC in the two groups significantly increased by 40 min and gradually and significantly decreased toward the respective exhaustion point. The decline in BGC from the peak at 40 min was significantly slower in the TAU group. The time when the once-increased BGC regressed to the 0-time level was significantly and positively correlated with exercise time until exhaustion. At the 120-min point, where the difference in BGC between the two groups was most significant, plasma free fatty acid concentration and acetyl-carnitine and N-acetyltaurine concentrations in skeletal muscle were significantly higher in the TAU group, whereas glycogen and glucogenic amino acid concentrations and G6Pase activity in the liver were not different between the two groups. Taurine supplementation enhances endurance capacity by delaying the decrease in BGC toward exhaustion through increases of lipolysis in adipose tissues and fatty acid oxidation in skeletal muscles during endurance exercise.

Keywords:  Blood glucose concentration; Endurance exercise; Fatty acid oxidation; Gluconeogenesis; Jugular vein cannulation; Lipolysis; Taurine

DOI:  https://doi.org/10.1007/s00726-021-03110-8
Sci Rep. 2022 Jan 31. 12(1): 1635

Effect of endurance training and PGC-1α overexpression on calculated lactate production volume during exercise based on blood lactate concentration.

Reo Takeda, Yudai Nonaka, Katsuyuki Kakinoki, Shinji Miura, Yutaka Kano, Daisuke Hoshino.

Lactate production is an important clue for understanding metabolic and signal responses to exercise but its measurement is difficult. Therefore, this study aimed (1) to develop a method of calculating lactate production volume during exercise based on blood lactate concentration and compare the effects between endurance exercise training (EX) and PGC-1α overexpression (OE), (2) to elucidate which proteins and enzymes contribute to changes in lactate production due to EX and muscle PGC-1α OE, and (3) to elucidate the relationship between lactate production volume and signaling phosphorylations involved in mitochondrial biogenesis. EX and PGC-1α OE decreased muscle lactate production volume at the absolute same-intensity exercise, but only PGC-1α OE increased lactate production volume at the relative same-intensity exercise. Multiple linear regression revealed that phosphofructokinase, monocarboxylate transporter (MCT)1, MCT4, and citrate synthase equally contribute to the lactate production volume at high-intensity exercise within physiological adaptations, such as EX, not PGC-1α OE. We found that an exercise intensity-dependent increase in the lactate production volume was associated with a decrease in glycogen concentration and an increase in P-AMPK/T-AMPK. This suggested that the calculated lactate production volume was appropriate and reflected metabolic and signal responses but further modifications are needed for the translation to humans.

DOI: https://doi.org/10.1038/s41598-022-05593-1
Neoplasia. 2022 Jan 31. pii: S1476-5586(22)00002-1. [Epub ahead of print]25 28-40

The GSK3 kinase and LZTR1 protein regulate the stability of Ras family proteins and the proliferation of pancreatic cancer cells.

Chitra Palanivel, Neha Chaudhary, Parthasarathy Seshacharyulu, Jesse L Cox, Ying Yan, Surinder K Batra, Michel M Ouellette.

  Ras family proteins are membrane-bound GTPases that control proliferation, survival, and motility. Many forms of cancers are driven by the acquisition of somatic mutations in a RAS gene. In pancreatic cancer (PC), more than 90% of tumors carry an activating mutation in KRAS. Mutations in components of the Ras signaling pathway can also be the cause of RASopathies, a group of developmental disorders. In a subset of RASopathies, the causal mutations are in the LZTR1 protein, a substrate adaptor for E3 ubiquitin ligases that promote the degradation of Ras proteins. Here, we show that the function of LZTR1 is regulated by the glycogen synthase kinase 3 (GSK3). In PC cells, inhibiting or silencing GSK3 led to a decline in the level of Ras proteins, including both wild type Ras proteins and the oncogenic Kras protein. This decline was accompanied by a 3-fold decrease in the half-life of Ras proteins and was blocked by the inhibition of the proteasome or the knockdown of LZTR1. Irrespective of the mutational status of KRAS, the decline in Ras proteins was observed and accompanied by a loss of cell proliferation. This loss of proliferation was blocked by the knockdown of LZTR1 and could be recapitulated by the silencing of either KRAS or GSK3. These results reveal a novel GSK3-regulated LZTR1-dependent mechanism that controls the stability of Ras proteins and proliferation of PC cells. The significance of this novel pathway to Ras signaling and its contribution to the therapeutic properties of GSK3 inhibitors are both discussed.

Keywords:  GSK3; LZTR1; Pancreatic cancer; Protein stability; RAS

DOI:  https://doi.org/10.1016/j.neo.2022.01.002
Food Funct. 2022 Feb 02.

Leucine supplementation during late gestation globally alters placental metabolism and nutrient transport via modulation of the PI3K/AKT/mTOR signaling pathway in sows.

Chang Cui, Caichi Wu, Jun Wang, Xiaoyu Zheng, Ziwei Ma, Pengwei Zhu, Wutai Guan, Shihai Zhang, Fang Chen.

In a previously published study we reported that sow dietary leucine supplementation during late pregnancy significantly improved newborn piglet birth weight by stimulating protein synthesis in the longissimus dorsi muscle. However, there is still limited knowledge as to whether leucine can exert its effects on the placenta, one of the most important temporal organs during pregnancy, to promote maternal-fetal nutrient supply and thus contribute to fetal intrauterine development. Therefore, we tested this hypothesis in the present study. In total, 150 sows at day 90 of gestation were divided into three groups and fed with either a control diet (CON), CON + 0.4% Leu or CON + 0.8% Leu, respectively, until parturition. Placental metabolomics, full spectrum amino acids and nutrient transporters were systematically analyzed after sample collection. The results indicated that Leu supplementation led to an altered placental metabolism with an increased number of metabolites related to glycolysis and the oxidation of fatty acids, as well as elevated levels of amino acid accumulation in the placenta. In addition, nutrient transporters of amino acids, glucose and fatty acids in the placenta were globally up-regulated and several enzymes related to energy metabolism, including hexokinase, succinate dehydrogenase, lactated hydrogenase, glycogen phosphorylase and hydroxyacyl-CoA-dehydrogenase, were also significantly increased with no change observed in the antioxidative status of those groups with Leu supplementation. Furthermore, the phosphorylation of PI3K, Akt, and mTOR was enhanced in the placenta of sows undergoing Leu treatment. Collectively, we concluded that supplementing the diets of sows with Leu during late gestation globally altered placental metabolism and promoted maternal-fetus nutrient transport (amino acids, glucose, and fatty acids) via modulation of the PI3K/Akt/mTOR signaling pathway.

DOI: https://doi.org/10.1039/d1fo04082k
Environ Sci Pollut Res Int. 2022 Jan 29.

Investigation of potential behavioral and physiological effects of caffeine on D. magna.

Bruno Nunes, João Santos, Ricardo Dionísio, Gilberto Dias de Alkimin.

  With the ever-increasing consumption of pharmaceutical compounds, their presence in the environment is now an undisputable reality. The majority of these compounds are released into the wild after their therapeutic use, as biotransformation products or in their original form. The presence of this class of compounds in the environment, due to their biological properties, can exert effects on non-target organisms, with adverse consequences. In addition, some bioactive substances, such as stimulants of the central nervous system, are also used by humans as part of their diet. The adverse consequences posed by such chemicals may be permanent or transient, if the exposure to xenobiotics is halted; it is thus of the paramount importance to study effects that result from long-term exposure to toxicants, but also the recovery of organisms previously exposed to such substances, especially if such chemicals may cause some type of addiction. Caffeine (1,3,7-trimethylxanthine) is a naturally occurring alkaloid found in many plants, being one of the most common stimulant/pharmaceutical compounds found in the environment. In addition, it is addictive, and strongly consumed by humans, a factor that contributes also for its continuous presence in the aquatic environment. The aim of this study was to evaluate the effects of environmentally relevant concentrations (0.08; 0.4; 2; 10; and 50 μg/L) of caffeine on behavior and physiological parameters (that are proxies of metabolic traits, such as oxygen uptake and glycogen content), in individuals of the freshwater crustacean species Daphnia magna, of distinct ages, and with or without a recovery period in the absence of caffeine. Regarding behavior, the results indicated that caffeine exposure altered the moved distance of the test organisms, but not according to a coherent pattern; low concentrations of caffeine reduced the movement of exposed daphnids, while higher levels did not have any measurable effect on this parameter. In addition, it was possible to identify subtle withdrawal effects (animals exposed to caffeine during 21 days and kept in uncontaminated media for 2 days). Regarding the other two studied parameters, caffeine exposure did not result in any significant modification in oxygen uptake and glycogen stores/reserves of the test organisms, in animals continuously exposed, or in those subjected to a recovery period, suggesting that despite a behavioral stimulatory effect, this was not followed by any metabolic change, and no addictive effect was possible to infer. The results showed that the presence of caffeine in environmental concentrations can induce mild behavioral effects at low, albeit realistic levels, but not capable of establishing clear biochemical changes.

Keywords:  Behavior; Caffeine; Daphnia magna; Glycogen; Pharmaceutical compounds; Respirometry

DOI:  https://doi.org/10.1007/s11356-022-18695-0
Transl Cancer Res. 2020 May;9(5): 3691-3702

PNMA5 knockdown suppresses the proliferation, invasion, and metastasis of epithelial ovarian cancer cells.

Haifeng Qiao, Jinwei Liu, Zhixia Yang, Leilei Gao, Xiaolan Zhang, Guangping Lu, Yinglei Liu, Manhua Liu, Xiaoyan Ying, Dong Zhang.

  Background: Ovarian cancer is a severe gynecological malignancy. Paraneoplastic Ma antigen 5 (PNMA5) is a confirmed tumor onconeural antigen, which has been screened as a female fertility factor. PNMA5 overexpression might serve as a marker of poor prognosis in colon cancer. Our earlier study showed that PNMA5 was essential for meiosis in mouse oocytes. In this study, we investigate the role and probable mechanism of PNMA5 in the occurrence and development of epithelial ovarian cancer (EOC).Methods: Immunochemistry and western blot analyses were used to verify PNMA5 overexpression in clinical EOC tissues and EOC cell line HO8910. A specific siRNA was used to reduce PNMA5 levels, and several proliferation and migration-related indexes were assessed. We also examined mitochondria, microfilaments, and several essential kinases.
Results: We found that the expression of PNMA5 in EOC tissues was significantly higher than that in benign ovarian tumors and healthy normal ovarian tissues and that this was strictly related to the FIGO stage and histological grade. PNMA5 expression in ovarian cancer cell line HO8910 was higher than that in the normal healthy ovarian cell line Moody. PNMA5 knockdown in HO8910 cells not only inhibited the proliferation, migration, invasion, cell cycle, and F-actin polymerization of HO8910 cells but also promoted early apoptosis and led to abnormal distribution and accumulation of mitochondria. PNMA5 phosphorylation was found to be positively regulated by Src activity, and PNMA5 phosphorylation promoted the downstream glycogen synthase kinase-3β (GSK-3β) signaling pathway.
Conclusions: PNMA5 plays a pivotal role in the occurrence and development of EOC and is a potential marker of this disease.

Keywords:  Epithelial ovarian cancer (EOC); HO8910; invasion; paraneoplastic Ma antigen 5 (PNMA5); proliferation

DOI:  https://doi.org/10.21037/tcr-20-2013