Figure 7.

Schematic view of a hypothesis that the crosstalk of AR signaling pathway with PI3K-Akt-mTOR pathway facilitate de novo synthesis of cholesterol via activation of SREBPs and thereafter the androgen (testosterone) production increases in a neuroblastoma cell. In view of this hypothesis, a statin in cooperation with abiraterone acetate inhibits cholesterol and androgen production and therefore they turn on a repression of AR-SCAP-SREBPs-HMGCR-Cholosterol-CYP17A1-Androgen positive feedback loop. VEGF-mediated angiogenesis in MYCN-amplified NB cells depends on PI3K/Akt-driven signaling that most likely bypasses mTOR (43), while inhibition of AR signaling by combined statins with AA is likely independent of MYCN status. Yellow arrow, activation, induction, up-regulation, or directions of movements; red drumstick, inhibition; dashed blue arrow, synthetic route of cholesterol and androgen under the control of key enzymes. HMGCS, HMGCR, FDPS, and CYP17A1, all of them are transcriptionally regulated by SREBP-n (N-terminal of SREBPs); SRE, sterol response element; ARE, androgen receptor response element.