PI3K/AKT Signaling Tips the Balance of Cytoskeletal Forces for Cancer Progression

SIMPLE SUMMARY: The PI3K/AKT signaling pathway plays critical roles in regulating a series of cellular changes to promote tumor development and progression. The cytoskeletal network, comprising of the microfilaments, microtubules, and intermediate filaments, is known to be regulated by signaling cascades, which lead to dissemination of primary tumors and thus worsen clinical outcomes. Both aberrant activation of the PI3K/AKT pathway and alteration of cytoskeletal structures are highly prevalent in cancer cells. However, it is not fully understood how the crosstalk and feedback between PI3K and the cytoskeleton could cooperatively lead to cancer progression and a poorer patient prognosis. Herein, we discuss the molecular and cellular regulation between cytoskeletal proteins and the PI3K/AKT signaling pathway, and how these two orchestrate a regulatory process that aids cancer progression. Our review also summarizes recent advances in the clinical development of PI3K and cytoskeleton targeting agents, thereby providing insight into the development of novel therapeutic approaches targeting the interplay between PI3K and the cytoskeleton for cancer management. ABSTRACT: The PI3K/AKT signaling pathway plays essential roles in multiple cellular processes, which include cell growth, survival, metabolism, and motility. In response to internal and external stimuli, the PI3K/AKT signaling pathway co-opts other signaling pathways, cellular components, and cytoskeletal proteins to reshape individual cells. The cytoskeletal network comprises three main components, which are namely the microfilaments, microtubules, and intermediate filaments. Collectively, they are essential for many fundamental structures and cellular processes. In cancer, aberrant activation of the PI3K/AKT signaling cascade and alteration of cytoskeletal structures have been observed to be highly prevalent, and eventually contribute to many cancer hallmarks. Due to their critical roles in tumor progression, pharmacological agents targeting PI3K/AKT, along with cytoskeletal components, have been developed for better intervention strategies against cancer. In our review, we first discuss existing evidence in-depth and then build on recent advances to propose new directions for therapeutic intervention.