Enhanced Sestrin expression through Tanshinone 2A treatment improves PI3K-dependent inhibition of glioma growth

Glioblastomas really are a highly aggressive cancer type which respond poorly to current pharmaceutical treatments, thus novel therapeutic approaches have to be investigated. One particular approach involves using the bioactive natural product Tanshinone IIA (T2A) produced from china plant Danshen, where mechanistic insight with this anti-cancer agent is required to validate its use. Here, we use a tractable model system, Dictyostelium discoideum, to supply this insight. T2A potently inhibits cellular proliferation of Dictyostelium, suggesting molecular targets within this model. We reveal that T2A quickly reduces phosphoinositide 3 kinase (PI3K) and protein kinase B (PKB) activity, but surprisingly, the downstream complex mechanistic target of rapamycin complex 1 (mTORC1) is just inhibited following chronic treatment. Investigating regulators of mTORC1, including PKB, tuberous sclerosis complex (TSC), and AMP-activated protein kinase (AMPK), suggests these enzymes weren’t accountable for this effect, implicating yet another molecular mechanism of T2A. We identify this mechanism because the elevated expression of sestrin, an Paxalisib adverse regulator of mTORC1. We further reveal that combinatory treatment utilizing a PI3K inhibitor and T2A brings about a synergistic inhibition of cell proliferation. Then we translate our findings to human and mouse-derived glioblastoma cell lines, where both a PI3K inhibitor (Paxalisib) and T2A reduces glioblastoma proliferation in monolayer cultures as well as in spheroid expansion, with combinatory treatment considerably enhancing this effect. Thus, we advise a brand new method for cancer treatment, including glioblastomas, through combinatory treatment with PI3K inhibitors and T2A.