Specific mitochondrial calcium overload induces mitochondrial fission in prostate cancer cells

Abstract

Abstract. Mitochondria are structurally complex organelles that undergo fragmentation or fission in apoptotic cells. Mitochondrial fission requires the cytoplasmic dynamin-related protein, Drp1, which translocates to the mitochondria during apoptosis and interacts with the mitochondrial protein, Fis1. Finely tuned changes in cellular calcium modulate a variety of intracellular functions; in resting cells, the level of mitochondrial calcium is low, while it is higher during apoptosis. Mitochondria take up Ca 2+ via the Uniporter and extrude it to the cytoplasm through the mitochondrial Na + /Ca 2+ exchanger. Overload of Ca 2+ in the mitochondria leads to their damage, affecting cellular function and survival. The mitochondrial Na + /Ca 2+ exchanger was blocked by benzodiazepine, CGP37157 (CGP) leading to increased mitochondrial calcium and enhancing the apoptotic effects of TRAIL, TNF· related apoptosis inducing ligand. In the present study, we observed that increasing mitochondrial calcium induced mitochondrial fragmentation, which correlated with the presence of Drp1 at the mitochondria in CGP treated cells. Under these conditions, we observed interactions between Drp1 and Fis1. The importance of Drp1 in fragmentation was confirmed by transfection of dominant negative Drp1 construct. However, fragmentation of the mitochondria was not sufficient to induce apoptosis, although it enhanced TRAIL-induced apoptosis. Furthermore, oligomerization of Bak was partially responsible for the increased apoptosis in cells treated with both CGP and TRAIL. Thus, our results show that combination of an apoptogenic agent and an appropriate calcium channel blocker provide therapeutic advantages.

Oestrogen action on thyroid progenitor cells: relevant for the pathogenesis of thyroid nodules?

“…Similar results were observed before in differentiated human thyroid cells (Manole et al 2001). In addition, overexpression of cyclin D1 was detected in several papillary thyroid carcinomas (Lazzereschi et al 1998, Shi et al 2001, Khoo et al 2002, Kumar et al 2010.…”

“…Benign and malignant thyroid cells and tissues express functional oestrogen receptors (ERs) and their growth is stimulated by oestrogen (Furlanetto et al 1999, Manole et al 2001, Ceresini et al 2006, Kumar et al 2010, Rajoria et al 2010, Di Vito et al 2011. In addition, the presence of these receptors has also been demonstrated in thyroid vessels that may be relevant for the vascularization of neoplastic tissues (Ceresini et al 2006).…”

Estrogen and its role in thyroid cancer

“…These cells express functional ERs and enhance DNA synthesis and proliferation in response to E 2 stimulation. Similar results were obtained in thyroid cells derived from goiter nodules and in human thyroid carcinoma cells (Manole et al 2001, Zeng et al 2007, Kumar et al 2010, Rajoria et al 2010). E 2 -stimulated cell growth was associated with increased expression of cyclin D1 protein, which plays a key role in the regulation of the G1/S transition in the cell cycle (Motokura & Arnold 1993, Manole et al 2001.…”

“…The strongest support for estrogen as a risk factor of differentiated thyroid cancer comes from experimental studies that have clearly demonstrated that E 2 , the main female sex hormone, is a potent stimulator of both human benign and malignant thyroid cells (Manole et al 2001, Zeng et al 2007, Chen et al 2008, Kumar et al 2010, Rajoria et al 2010. Interestingly, E 2 was equally potent in its growth-promoting effect on human thyroid cells derived from male and female thyroid glands, which underlines the relevance of the hormone rather than of other sex-specific factors (Manole et al 2001).…”

Obesity and thyroid cancer

“…Investigations with thyroid cancer cell lines and also some human thyroid tumors have demonstrated the expression of ERs in thyroid tumor cells, both neoplastic and non-neoplastic, indicating that thyroid cells are likely to experience effects of estrogen or ERs (Lee et al 2005, Zeng et al 2007. In fact, the administration of estrogen has been associated with thyroid cell growth and proliferation and also with some changes in other markers of proliferation, growth, and angiogenesis, demonstrating not only the intracellular role of estradiol and ERs, but also their role in the transcription of other genes (Tangjitgamol et al 2005, Zeng et al 2007, Ranks et al 2009, Kavanagh et al 2010, Kumar et al 2010, Rajoria et al 2010, Kamat et al 2011. A recent study has demonstrated crosstalk between ER and PPARg, indicating that levels of expression of ERa (ESR1) and ERb (ESR2) are related to PPARg levels in the cell.…”