Phosphoinositide 3-hydroxide kinase blockade enhances apoptosis in the Ewing's sarcoma family of tumors.

摘要: Ewing's sarcoma family of tumors (ESFTs) affects patients between the ages 3 and 40 years, with most cases occurring in second decade life. These contain a characteristic translocation, t(11;22), that produces unique fusion protein, EWS/FLI-1. EWS/FLI-1 transforms mouse fibroblasts; this transformation requires intact EWS FLI-1 domains as well insulin-like growth factor-I receptor (IGF-IR). The IGF-IR is well-described transmembrane tyrosine kinase modulates transformation, cell growth, survival. survival signaling mediated through downstream activation phosphoinositide 3-OH (PI 3-K) Akt. Apoptosis, programmed death, progresses from central death signal to caspase cascade, including caspase-3. Because has been shown play role ESFTs, we wanted determine molecules cellular response doxorubicin treatment. Doxorubicin increased caspase-3 activity two ESFT lines, TC-32 TC-71. Concomitant treatment doxorubicin-treated cells IGF-I reduced 8-fold 4-fold To whether PI 3-K IGF-I-mediated was then inhibited wortmannin LY294002. number enhanced apoptosis compared noninhibited cells. Akt, serine/threonine activated 3-K, investigated its constitutive would render more resistant doxorubicin. A constitutively Akt stably transfected into those high levels expression demonstrated resistance doxorubicin-induced activation. results indicate lines use an initiated pathway for when treated