Cisplatin Hypersensitivity of Testicular Germ Cell Tumors Is Determined by High Constitutive Noxa Levels Mediated by Oct-4

Abstract

Testicular germ cell tumors (TGCT) are considered a paradigm of chemosensitive tumors. Embryonal carcinoma cells represent the pluripotent entity of TGCTs and are characterized by expression of Oct-4, a key regulator of pluripotency and a determinant of their inherent hypersensitivity to cisplatin. However, the mechanisms underlying this Oct-4-mediated sensitivity are poorly understood. We previously showed that p53 is a major player in cisplatin hypersensitivity and therefore investigated whether Oct-4 may directly affect p53 activity. Despite a significant decrease in sensitivity, depletion of Oct-4 neither did alter cisplatin-induced transactivation of p53 target genes nor its subcellular localization. These data indicate that, rather than directly modulating p53 activity, Oct-4 provides a cellular context that augments the proapoptotic activity of p53. As mitochondrial priming by the Bcl-2 family is a known determinant of chemosensitivity, we compared the constitutive levels of these proteins in Oct-4-positive and -depleted cells. We identified Noxa as the only Bcl-2 family protein to be highly correlated with Oct-4 status and cisplatin sensitivity. Compared with differentiated cells, constitutive Noxa levels were significantly higher in Oct-4-positive cell lines and cancer patient samples. Furthermore, RNA interference-mediated knockdown of Oct-4 resulted in reduced Noxa transcript, in an almost complete loss of constitutive Noxa protein and decreased cisplatin hypersensitivity to a similar extent as did Noxa depletion. In conclusion, our study indicates that Noxa is a central determinant of hypersensitivity to cisplatin. Oct-4-dependent high constitutive levels of this BH3-only protein prime embryonal carcinoma cells to undergo rapid and massive apoptosis in response to p53 activation. Cancer Res; 73(5);

Novel combination of mitochondrial division inhibitor 1 (mdivi-1) and platinum agents produces synergistic pro-apoptotic effect in drug resistant tumor cells

“…Noxa, a member of the pro-apoptotic BH3-only Bcl-2 protein family, can be induced by cisplatin [30], and promotes MOMP through Bax or Bak-mediated mechanisms [26]. The level of Noxa has been shown to be a central determinant of hypersensitivity to cisplatin in testicular germ cell tumors [31]. In addition, induction of Noxa is able to enhance the sensitivity of ovarian cancer cells to cisplatin [32].…”

Differential DNA damage signalling and apoptotic threshold correlate with mouse epiblast-specific hypersensitivity to radiation

“…Unfortunately, no antibody was available to test the levels of Noxa protein expression. Interestingly, Gutekunst and colleagues reported an Oct4-mediated Noxa upregulation in testicular germ cell tumours, rendering them hypersensitive to cisplatin treatment (Gutekunst et al, 2013). The apoptotic threshold is depicted as a balance, the equilibrium of which is impacted by the ratio between pro-and anti-apoptotic factors.…”

An oncofetal and developmental perspective on testicular germ cell cancer

“…This allows rapid growth while protecting ES/germ line genomic integrity [195]. In TGCC this behavior is mirrored: high TP53 expression is associated with cisplatin sensitivity specifically in the presence of low p21 [273,[284][285][286][287][288][289][290][291]. A number of other downstream targets of G1/S cell cycle progression have been identified as mechanistic in TGCC cisplatin response.…”