A multiprotein signaling complex sustains AKT and mTOR/S6K activity necessary for the survival of cancer cells undergoing stress.

Cancer cells encounter stresses during tumor progression and metastatic spread, however, how they survive these challenges is not fully understood. We now identify a mechanism for cancer cell survival through the discovery of a multiprotein signaling complex that includes the GTPase Cdc42, the Cdc42 GEF/effector protein Dock7, AKT, mTOR and the mTORC1 regulatory partners TSC1, TSC2, and Rheb. This pro-survival signaling complex sustains the activated state of AKT by preventing its dephosphorylation at Ser473 during serum starvation, resulting in a low but critical activation of a Raptor-independent mTOR/S6K activity. We demonstrate that the Dock7 DHR1 domain, previously of unknown function, is responsible for preserving AKT phosphorylation through an interaction requiring its C2-like motif. Collectively, these findings help address long-standing questions of how Cdc42 signals mTOR activation by elucidating the unique functions of its signaling partner Dock7 as an AKT regulator necessary for resistance to anoikis and apoptosis in cancer cells.

Small molecule based EGFR targeting of biodegradable nanoparticles containing temozolomide and Cy5 dye for greatly enhanced image-guided glioblastoma therapy.

Current glioblastoma multiforme (GBM) treatment is insufficient, facing obstacles like poor tumor accumulation and dose limiting side effects of chemotherapeutic agents. Targeted nanomaterials offer breakthrough potential in GBM treatment; however, traditional antibody-based targeting poses challenges for live brain application. To overcome current obstacles, we introduce here the development of a small molecule targeting agent, CFMQ, coupled to biocompatible chitosan coated poly(lactic-co-glycolic) acid nanoparticles. These targeted nanoparticles enhance cellular uptake and show rapid blood-brain barrier (BBB) permeability in-vitro, demonstrating the ability to effectively deliver their load to tumor cells. Encapsulation of the chemotherapeutic agent, temozolomide (TMZ), decreases the IC50 ~34-fold compared to free-drug. Also, CFMQ synergistically suppresses tumor cell progression, reducing colony formation (98%), cell migration (84%), and cell invasion (77%). Co-encapsulation of Cy5 enables optical image guided therapy. This biocompatible theranostic nanoformulation shows early promise in significantly enhancing the efficacy of TMZ, while providing potential for image-guided therapy for GBM.

Blast-induced injury responsive relative gene expression of traumatic brain injury biomarkers in human brain microvascular endothelial cells.

Disruption of the blood-brain barrier (BBB) is a critical component of traumatic brain injury (TBI) progression. However, further research into the mechanism of BBB disruption and its specific role in TBI pathophysiology is necessary. To help make progress in elucidating TBI affected BBB pathophysiology, we report herein relative gene expression of eleven TBI biomarkers and other factors of neuronal function in human brain microvascular cells (HBMVEC), one of the main cell types in the BBB. Our in-vitro blast TBI model employs a custom acoustic shock tube to deliver injuries of varying intensities to HBMVECs in culture. Each of the investigated genes exhibit a significant change in expression as a response to TBI, which is dependent on both the injury intensity and time following the injury. This data suggests that cell signaling of HBMVECs could be essential to understanding the interaction of the BBB and TBI pathophysiology, warranting future investigation.