Human pheochromocytoma cancer cells as a plausible model of mitochondrial complex II-linked tumorigenesis
Author(s)
Vanova, Katerina
Krobova, Linda
Bezawork-Geleta, Ayenachem
Boukalova, Stepana
Pacak, Karel
Ghayee, Hans Kumar
Rohlena, Jakub
Neuzil, Jiri
Griffith University Author(s)
Year published
2019
Metadata
Show full item recordAbstract
Pheochromocytoma and paraganglioma (PHEO/PGL) are neuroendocrine tumours that are frequently associated with mutations in mitochondrial complex II (CII) subunits SDHA‐D. Clinical data indicate that SDHB‐deficient PHEO/PGL are less proliferative but are associated with higher invasiveness and metastasis. We have previously shown that both the loss of SDHB and/or depletion of mitochondrial (mt)DNA in the breast cancer cell line MDA‐MB‐231 leads to alternative assembly of CIIlow, which maintains homeostatic control of metabolite synthesis under bioenergetics stress and supports tumour growth. However, PHEO/PGL malignancies arise ...
View more >Pheochromocytoma and paraganglioma (PHEO/PGL) are neuroendocrine tumours that are frequently associated with mutations in mitochondrial complex II (CII) subunits SDHA‐D. Clinical data indicate that SDHB‐deficient PHEO/PGL are less proliferative but are associated with higher invasiveness and metastasis. We have previously shown that both the loss of SDHB and/or depletion of mitochondrial (mt)DNA in the breast cancer cell line MDA‐MB‐231 leads to alternative assembly of CIIlow, which maintains homeostatic control of metabolite synthesis under bioenergetics stress and supports tumour growth. However, PHEO/PGL malignancies arise from the chromaffin tissue; it is therefore expected that the epithelial‐derived cells, such as breast cancer cells, are not an optimal model to decipher the consequences of CII mutations in PHEO/PGL. For this reason, human chromaffin‐derived pheochromocytoma cancer cells line hPheo1 was used to introduce SDHB deficiency (SDHB KO cells) by gene manipulation. PGL tissue, mitochondria, and whole cell lysate were used for respiratory assay, native blue gel electrophoresis (NBGE) and western blotting. Similar to patient‐derived SDHB‐deficient paraganglioma tissue, SDHB KO cells featured substantial CII low in the absence of fully assembled CII on NBGE, accompanied by prominent decrease of respiration and other relevant alterations. Further analysis of this unique model is ongoing. Our data provide a new insight into pathological features of hard‐to‐treat SDHx‐related PHEO/PGL. We suggest that the existence of CIIlow in patients with SDHB‐mutated paraganglioma substantially contributes to tumorigenicity, and interference with CIIlow could ameliorate severe pathological outcomes, including enhanced migration and invasiveness.
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View more >Pheochromocytoma and paraganglioma (PHEO/PGL) are neuroendocrine tumours that are frequently associated with mutations in mitochondrial complex II (CII) subunits SDHA‐D. Clinical data indicate that SDHB‐deficient PHEO/PGL are less proliferative but are associated with higher invasiveness and metastasis. We have previously shown that both the loss of SDHB and/or depletion of mitochondrial (mt)DNA in the breast cancer cell line MDA‐MB‐231 leads to alternative assembly of CIIlow, which maintains homeostatic control of metabolite synthesis under bioenergetics stress and supports tumour growth. However, PHEO/PGL malignancies arise from the chromaffin tissue; it is therefore expected that the epithelial‐derived cells, such as breast cancer cells, are not an optimal model to decipher the consequences of CII mutations in PHEO/PGL. For this reason, human chromaffin‐derived pheochromocytoma cancer cells line hPheo1 was used to introduce SDHB deficiency (SDHB KO cells) by gene manipulation. PGL tissue, mitochondria, and whole cell lysate were used for respiratory assay, native blue gel electrophoresis (NBGE) and western blotting. Similar to patient‐derived SDHB‐deficient paraganglioma tissue, SDHB KO cells featured substantial CII low in the absence of fully assembled CII on NBGE, accompanied by prominent decrease of respiration and other relevant alterations. Further analysis of this unique model is ongoing. Our data provide a new insight into pathological features of hard‐to‐treat SDHx‐related PHEO/PGL. We suggest that the existence of CIIlow in patients with SDHB‐mutated paraganglioma substantially contributes to tumorigenicity, and interference with CIIlow could ameliorate severe pathological outcomes, including enhanced migration and invasiveness.
View less >
Conference Title
European Journal of Clinical Investigation
Volume
49
Issue
S1
Publisher URI
Subject
Clinical sciences
Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
Medicine, Research & Experimental
General & Internal Medicine