Abstract

Targeting Cancer at the Nuclear Pore

Asfar Azmi, Assistant Professor, Wayne State University School of Medicine

Trafficking of biological materials across nuclear membrane is an evolutionarily conserved mechanism that maintains normal eukaryotic cell homeostasis. Smaller entities can enter and exit the nuclear pore through diffusion. The movement of most of the proteins however, requires active transport that is mediated by specialized carriers called Karyopherins that maintain proper compartmentalization of micro- and macro-molecules. Such energy dependent trafficking occurs through the nuclear pore complex (NPC) that is embedded in the nuclear membrane. This is functionally critical for tumor suppressor proteins (TSPs) and transcription factors (TFs) that require nuclear retention and sequence specific DNA alignment to modulate their target gene expression or conduct genome surveillance activity. Indeed, cancer cells have evolved methods to disturb the nuclear traffic by abnormal expression of the nuclear exporters particularly exportin 1 (Xpo1) that leads to a cascade of de-regulations favoring uncontrolled growth and loss of surveillance within the cells. Recently, specific inhibitors of nuclear export (SINE) have been developed as a broad form of therapy targeting global re-alignment of multiple TSPs in the correct cellular compartment through inhibition of Xpo1 to rein in cancer. SINEs are under extensive Phase I and Phase II clinical evaluation for various tumor indications.