Emerging roles of F-box proteins in cancer drug resistance

Chemotherapy continues to be a major treatment strategy for various human malignancies. However, the frequent emergence of chemoresistance compromises chemotherapy efficacy leading to poor prognosis. Thus, overcoming drug resistance is pivotal to achieve enhanced therapy efficacy in various cancers. Although increased evidence has revealed that reduced drug uptake, increased drug efflux, drug target protein alterations, drug sequestration in organelles, enhanced drug metabolism, impaired DNA repair systems, and anti-apoptotic mechanisms, are critically involved in drug resistance, the detailed resistance mechanisms have not been fully elucidated in distinct cancers. Recently, F-box protein (FBPs), key subunits in Skp1-Cullin1-F-box protein (SCF) E3 ligase complexes, have been found to play critical roles in carcinogenesis, tumor progression, and drug resistance through degradation of their downstream substrates. Therefore, in this review, we describe the functions of FBPs that are involved in drug resistance and discuss how FBPs contribute to the development of cancer drug resistance. Furthermore, we propose that targeting FBPs might be a promising strategy to overcome drug resistance and achieve better treatment outcome in cancer patients. Lastly, we state the limitations and challenges of using FBPs to overcome chemotherapeutic drug resistance in various cancers.