nostic marker in combination using the Ki67 index [59].et al. identified that the hyexpression is actually a prognostic marker in combination with the Ki67 index [59]. However, pothesis that SOAT1 expression might be a clinically valuable marker for predicting treatthe hypothesis that SOAT1 expression confirmed by further studies [27,60]. Weigand et ment response to mitotane has not beencould be a clinically valuable marker for predicting treatment response to mitotane has not been confirmed ACC treated with mitotane in 12 al. retrospectively analyzed data of 231 patients with by additional studies [27,60]. Weigand et al. retrospectively analyzed data of 231 patients with ACC treated with mitotane in reference centers and didn’t locate any important differences involving tumors with higher 12 low SOAT1 expression in terms obtain any significant differences among tumors with or reference centers and didn’t of recurrence-free survival (in 158 sufferers treated with high or low SOAT1 progression-free survival (in 73 patients with (in 158 patients or disadjuvant mitotane), expression with regards to recurrence-free survivaladvanced ACC), treated with adjuvant mitotane), both settings) [60]. ease-specific survival (in progression-free survival (in 73 individuals with sophisticated ACC), or disease-specific survival (in both settings) [60].Physiological regulation of cholesterol uptake, synthesis, and steroidogenesis and proposed mitotane efFigure 2. Physiological regulation of cholesterol uptake, synthesis, and steroidogenesis and proposed mitotane effect/mechanism of action. Inside the the left element offigure is indicated the physiological mechanism that regulates the absorpfect/mechanism of action. In left element on the the figure is indicated the physiological mechanism that regulates the tion/synthesis of cholesterol and steroidogenesis. As depicted in thein the rightof the figure, mitotane AMPK Molecular Weight induces in vitro the absorption/synthesis of cholesterol and steroidogenesis. As depicted appropriate portion component from the figure, mitotane induces in vitro dissociation of MAMs and and blockade of cholesterol transport/synthesis and steroidogenesis. Accumulation of free of charge chothe dissociation of MAMs the the blockade of cholesterol transport/synthesis and steroidogenesis. Accumulation of no cost lesterol in cells causes ERER tension, apoptosis, and cell death. The ADAM8 Molecular Weight action of mitotane for each enzymeis indicated by a red cholesterol in cells causes anxiety, apoptosis, and cell death. The action of mitotane for each and every enzyme is indicated by a red mark. Figures had been developed modifying an image set from Clever http://smart.servier/ (19 July 2021). mark. Figures were created modifying an image set from Sensible http://smart.servier/ (19 July 2021).In vitro, mitotane induces ER anxiety via inhibition of SOAT1, which results in the blockade of cholesterol synthesis and steroidogenesis, and this accumulation of free of charge cholesterol quickly becomes toxic for the cells (Figure two) [58,61]. Moreover, mitotane in H295R subclones reduces the expression of ABCA1, that is involved within the cellular efflux of cholesterol [62], and of SCARB1, which encodes for scavenger receptor B1 (SR-BI),Cancers 2021, 13,7 ofIn vitro, mitotane induces ER stress by means of inhibition of SOAT1, which leads to the blockade of cholesterol synthesis and steroidogenesis, and this accumulation of free cholesterol quickly becomes toxic to the cells (Figure two) [58,61]. Moreover, mitotane in H295R subclones reduces the expression of ABCA1, that is involved