Ultrastructure, Steroidogenic Potential, and Energy Metabolism of the Snell Adrenocortical Carcinoma 494

Kimmel, Gary L.; Péron, Fernand G.; Haksar, Ajai; Bedigian, E.; Robidoux, William F.; Lin, Ming-te

doi:10.1083/jcb.62.1.152

Cited by 15 publications

(2 citation statements)

References 29 publications

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“…The decreased expression of mitochondrial complex I was also validated in an extended series of clinical samples using western blot analysis, suggesting the deficiency of complex I in ACC. In line with these findings, Kimmel et al ( 51 ) previously demonstrated a poor oxygen uptake by the tumor mitochondria of the rat ACC 494 model using the tricarboxylic acid cycle substrates (α-ketoglutarate, malate and isocitrate), which led them to propose that the tumor mitochondria could be deficiency in the flavoprotein dehydrogeneases for NADH and NADPH oxidation. Notably, the effect of several anti-ACC drugs (mitotane, niclosamide and ATR-101) is also tightly linked to the disruption of mitochondrial function ( 52 - 54 ).…”

Section: Discussionmentioning

confidence: 70%

Altered expression of the IGF2‑H19 locus and mitochondrial respiratory complexes in adrenocortical carcinoma

et al. 2022

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Abnormalities of the insulin-like growth factor 2 (IGF2)-H19 locus with the overexpression of IGF2 are frequent findings in adrenocortical carcinoma (ACC). The present study assessed the expression of RNAs and microRNAs (miRNAs/miRs) from the IGF2-H19 locus using PCR-based methods in ACC and adrenocortical adenoma (ACA). The results were associated with proteomics data. IGF2 was overexpressed in ACC, and its expression correlated with that of miR-483-3p and miR-483-5p hosted by IGF2. The downregulated expression of H19 in ACC compared to ACA correlated with miR-675 expression hosted by H19. Several proteins exhibited an inverse correlation in expression and were predicted as targets of miR-483-3p, miR-483-5p or miR-675. Subsets of these proteins were differentially expressed between ACC and ACA. These included several proteins involved in mitochondrial metabolism. Among the mitochondrial respiratory complexes, complex I and IV were significantly decreased in ACC compared to ACA. The protein expression of NADH:ubiquinone oxidoreductase subunit C1 (NDUFC1), a subunit of mitochondrial respiratory complex I, was further validated as being lower in ACC compared to ACA and normal adrenals. The silencing of miR-483-5p increased NDUFC1 protein expression and reduced both oxygen consumption and glycolysis rates. On the whole, the findings of the present study reveal the dysregulation of the IGF2-H19 locus and mitochondrial respiration in ACC. These findings may provide a basis for the further understanding of the pathogenesis of ACC and may have potential values for diagnostics and treatment.

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Section: Discussionmentioning

confidence: 70%

Altered expression of the IGF2‑H19 locus and mitochondrial respiratory complexes in adrenocortical carcinoma

et al. 2022

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“…Fig. 7 shows the plasma membrane and closely packed mitochondria, with typical vesicular cristae (27) in a cell that was not exposed to lanthanum.…”

Section: U L T R a S T R U C T U R A L L O C A L I Z A T I O N O F L mentioning

confidence: 99%

Lanthanum: inhibition of ACTH-stimulated cyclic AMP and corticosterone synthesis in isolated rat adrenocortical cells.

Haksar¹,

Maudsley²,

Péron³

et al. 1976

The Journal of Cell Biology

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Lanthanum (La +++) is a well-known Ca ++ antagonist in a number of biological systems. It was used in the present study to examine the role of Ca ++ in the regulation of adenyl cyclase of the adrenal cortex by ACTH. In micromolar concentrations, La +++ inhibited both cyclic AMP and corticosterone response of isolated adrenal cortex cells to ACTH. However, a number of intracellular processes were not affected by La +++. These include the stimulation of steroidogenesis by dibutyryl cyclic AMP, conversion of several steroid precursors into corticosterone, and stimulation of the latter by glucose. Thus, inhibition of steroidogenesis by La +++ appears to be solely due to an inhibition of ACTH-stimulated cyclic AMP formation. Electron microscope examination showed that La +++ was localized on plasma membrane of the cells and did not appear to penetrate beyond this region. Since La +++ is believed to replace Ca ++ at superficial binding sites on the cell membrane, it is proposed that Ca ++ at these sites plays an important role in the regulation of adenyl cyclase by ACTH. Similarities in the role of Ca ++ in "excitation-contraction" coupling and in the ACTH-adenyl cyclase system raise the possibility that a contractile protein may be involved in the regulation of adenyl cyclase by those hormones which are known to require Ca ++ in the process.Studies on the cellular pharmacology of lanthanum (La §247 have shown that this ion is a specific antagonist of Ca + § in a number of biological systems. Almost all of the effects of La +++ on Ca++-dependent movements or reactions in intact cells have been explained by postulating that La +++ can replace Ca ++ at well-defined sites on the outer cell membrane (16,23,29,58). Because of this specificity in the site of its action, La ++ § appears to 0rovide a precise approach for the elucidation of Ca++-dependent processes. Besides t Deceased 8 August 1975. the well-documented effects on the Ca+ +-dependent "excitation-contraction" coupling in the muscle, reviewed recently by Weiss (57), La +++ has also been reported to affect "stimulus-secretion" coupling in a number of systems that are believed to require Ca ++ as the coupling agent. These include .catecholamine release from the adrenal medulla (8), histamine release from mast cells (14), and oxytocin-induced milk ejection from the mammary gland (30).The requirement of Ca ++ for the steroidogenic effect of ACTH as well as that of cyclic AMP has been known for many years (5,6,41). More

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Rat adrenocortical carcinoma 494: An integrated structural, stereological, and biochemical analysis

1978

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Snell adrenocortical tumor 494 was implanted into male Sprague-Dawley rats and recovered 7, 14, 21, 28 or 35 days following initial detection by palpation (7-10 days following transplantation). Electron microscopic, stereological and biochemical analyses of the tumor were compared to adrenals of normal animals to serve as a baseline for further studies of the effects of chemotherapeutic agents on tumor cells. Tumor cells possessed oval or elongated mitochondrial profiles with tubular cristae, one or two very large (greater than 5 micrometer) lipid droplets, abundant ribosomes and coated vesicles, and sparse rough and smooth endoplasmic reticulum. Stereologic evaluation revealed that tumor lipid volume was 41% and mitochondrial volume 29% that of the normal adrenal controls. Tumor nuclei were 2.5 times larger than adrenocortical nuclei while cellular volumes were similar. On a net weight basis, tumor cholesterol was 55%, cholesterol ester 2.2%, and lipid phosphate 25% of respective mean values for normal adrenal glands. The tumor cholesterol: cholesterol ester ratio progressively decreased with time but remained 18-fold greater than the normal adrenal. Plasma corticosterone levels in tumor-bearing rats were elevated 3-fold by 14 days and initial detection. The adrenals of the tumor-bearing host exhibited marked involution, the extent of which was directly related to tumor size.

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Ultrastructure, Steroidogenic Potential, and Energy Metabolism of the Snell Adrenocortical Carcinoma 494

Cited by 15 publications

References 29 publications

Altered expression of the IGF2‑H19 locus and mitochondrial respiratory complexes in adrenocortical carcinoma

Altered expression of the IGF2‑H19 locus and mitochondrial respiratory complexes in adrenocortical carcinoma

Lanthanum: inhibition of ACTH-stimulated cyclic AMP and corticosterone synthesis in isolated rat adrenocortical cells.

Rat adrenocortical carcinoma 494: An integrated structural, stereological, and biochemical analysis

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