Variation in mitochondrial function in hypoxia-sensitive and hypoxia-tolerant human glioma cells

We have shown previously that human glioblastoma multiforme cells vary in their ability to survive under hypoxic conditions. Under oxygen limiting conditions, hypoxia-tolerant cells decrease their oxygen consumption rate whereas hypoxia-sensitive cells continue to consume oxygen at a relatively steady rate until the oxygen supply becomes exhausted. We now show that hypoxia-tolerant and hypoxia-sensitive cells exhibit distinct patterns of mitochondrial function in response to hypoxic challenge. Hypoxia-tolerant cell lines retain stable mitochondrial membrane potential and ATP concentration when incubated under oxygen limiting conditions. In addition, hypoxia-tolerant cell lines are consistently more sensitive to a wide spectrum of inhibitors of mitochondrial function than are hypoxia-sensitive cells. In contrast, the hypoxia-sensitive cells are unable to maintain stable mitochondrial membrane potential and ATP levels when incubated at reduced oxygen tension. These results demonstrate significant differences in the mitochondrial function between these two phenotypes and reinforce previous data that suggest a regulatory role for mitochondria in the development of hypoxia tolerance

Investigation of the genes for RET and its ligand complex, GDNF/GFR alpha-1, in small cell lung carcinoma

RET is a receptor tyrosine kinase expressed in neuroendocrine cells and in tumors of these cell types. RET activation may be mediated by a ligand complex comprising glial cell line-derived neurotrophic factor (GDNF) and GDNF family receptor alpha-1 (GFR alpha-1). Activating RET mutations are found in the inherited cancer syndrome multiple endocrine neoplasia type 2 and in a subset of the related sporadic tumors, medullary thyroid carcinoma and pheochromocytoma, both being derived from neuroendocrine tissues, In one small study, mutations were identified in another tumor with neuroendocrine features, small cell lung carcinoma (SCLC), To determine whether RET mutations contribute to the pathogenesis of SCLC, we examined a panel of 54 SCLC cell lines. No mutations were identified in RET exons 10, I I, and 13-16, regions previously implicated in SCLC or other neuroendocrine tumors, We further examined the expression pattern of RET and the genes encoding the components of its ligand complex GDNF and GFR alpha-1, in 21 SCLC lines by using RT-PCR. Although we found no consistent pattern of expression for these three genes, RET was expressed in 57% of SCLC lines. Thus, although RET mutations appear unlikely to be an important step in the tumorigenesis of SCLC, the frequent expression of this gene suggests that RET may have a mitogenic role in a subset of SCLC cell lines, (C) 1998 Wiley-Liss, Inc

Investigation of the genes for RET and its ligand complex, GDNF/GFR alpha-1, in small cell lung carcinoma

RET is a receptor tyrosine kinase expressed in neuroendocrine cells and in tumors of these cell types. RET activation may be mediated by a ligand complex comprising glial cell line-derived neurotrophic factor (GDNF) and GDNF family receptor alpha-1 (GFR alpha-1). Activating RET mutations are found in the inherited cancer syndrome multiple endocrine neoplasia type 2 and in a subset of the related sporadic tumors, medullary thyroid carcinoma and pheochromocytoma, both being derived from neuroendocrine tissues, In one small study, mutations were identified in another tumor with neuroendocrine features, small cell lung carcinoma (SCLC), To determine whether RET mutations contribute to the pathogenesis of SCLC, we examined a panel of 54 SCLC cell lines. No mutations were identified in RET exons 10, I I, and 13-16, regions previously implicated in SCLC or other neuroendocrine tumors, We further examined the expression pattern of RET and the genes encoding the components of its ligand complex GDNF and GFR alpha-1, in 21 SCLC lines by using RT-PCR. Although we found no consistent pattern of expression for these three genes, RET was expressed in 57% of SCLC lines. Thus, although RET mutations appear unlikely to be an important step in the tumorigenesis of SCLC, the frequent expression of this gene suggests that RET may have a mitogenic role in a subset of SCLC cell lines, (C) 1998 Wiley-Liss, Inc