Figure 7. Possible mechanisms of action of CYP1A1 knock down.

CYP1A1 knock down by siRNA results in the dual inactivation ERK and AKT ⁽¹⁾. Inactivation of ERK could presumably remove the suppressive pressure that this exerts on LKB1 ⁽²⁾, thereby allowing activation of AMPK ⁽³⁾. LKB1-independent mechanisms may also be possible. Additionally, inhibition of AKT could result in the release of its suppressive effect on AMPK ⁽⁴⁾. Alternatively, inhibition of AKT by CYP1A1siRNA could result in the release of the TSC1/2 complex from suppression ⁽⁵⁾, followed by release of RHEB ⁽⁶⁾, and subsequent inhibition of mTOR signaling ⁽⁷⁾. Alternatively, AMPK could directly activate TSC2 ⁽⁵⁾ and inhibit RAPTOR ⁽⁷⁾, thereby inhibiting mTOR signaling⁽⁸⁾. In this manner CYP1A1siRNA treatment results in cell cycle arrest and increased apoptosis ⁽⁹⁾. In summary, we propose that CYP1A1siRNA-mediated inhibition of ERK1/2 and/or AKT results in AMPK activation, thereby inhibiting the mTOR/P70S6K pathway and thus resulting in cellular death. Legend: AMPK, AMP-activated protein kinase; ERK1/2, Extracellular Signal-Regulated Kinases 1 and 2; KSR, Kinase Suppressor of Ras; LKB1, Liver kinase B1; P70S6K, 70kDa ribosomal protein S6 kinase; RHEB, Ras homolog enriched in brain; TSC1/2, Tuberous sclerosis protein 1/2.