Targeting the "undruggable": RNA-binding proteins in the spotlight in cancer therapy.

Tumors refractory to conventional therapy belong to specific subpopulations of cancer cells, which have acquired a higher number of mutations/epigenetic changes than the majority of cancer cells. This property provides them the ability to become resistant to therapy. Aberrant expression of certain RNA-binding proteins (RBPs) can regulate the sensitivity of tumor cells to chemotherapeutic drugs by binding to specific regions present in the 3´-UTR of certain mRNAs to promote or repress mRNA translation or by interacting with other proteins (including RBPs) and non-coding RNAs that are part of ribonucleoprotein complexes. In particular, an increasing interest in the RBPs involved in chemoresistance has recently emerged. In this review, we discuss how RBPs are not only affected by chemotherapeutic treatments, but also play an active role in therapeutic responses via the direct modulation of crucial cancer-related proteins. A special focus is being placed on the development of therapeutic strategies targeting these RBPs.

RNA-binding proteins: Underestimated contributors in tumorigenesis.

mRNA export, translation, splicing, cleavage or capping determine mRNA stability, which represents one of the primary aspects regulating gene expression and function. RNA-binding proteins (RBPs) bind to their target mRNAs to regulate multiple cell functions by increasing or reducing their stability. In recent decades, studies of the role of RBPs in tumorigenesis have revealed an increasing number of proteins impacting the prognosis, diagnosis and cancer treatment. Several RBPs have been identified based on their interactions with oncogenes or tumor suppressor genes in human cancers, which are involved in apoptosis, the epithelial-mesenchymal transition (EMT), DNA repair, autophagy, cell proliferation, immune response, metabolism, and the regulation of noncoding RNAs. In this review, we propose a model showing how RBP mutations influence tumorigenesis, and we update the current knowledge regarding the molecular mechanism by which RBPs regulate cancer. Special attention is being devoted to RBPs that represent prognostic and diagnostic factors in cancer patients.

Insights into new mechanisms and models of cancer stem cell multidrug resistance.

The acquisition of genetic alterations, clonal evolution, and the tumor microenvironment promote cancer progression, metastasis and therapy resistance. These events correspond to the establishment of the great phenotypic heterogeneity and plasticity of cancer cells that contribute to tumor progression and resistant disease. Targeting resistant cancers is a major challenge in oncology; however, the underlying processes are not yet fully understood. Even though current treatments can reduce tumor size and increase life expectancy, relapse and multidrug resistance (MDR) ultimately remain the second cause of death in developed countries. Recent evidence points toward stem-like phenotypes in cancer cells, promoted by cancer stem cells (CSCs), as the main culprit of cancer relapse, resistance (radiotherapy, hormone therapy, and/or chemotherapy) and metastasis. Many mechanisms have been proposed for CSC resistance, such as drug efflux through ABC transporters, overactivation of the DNA damage response (DDR), apoptosis evasion, prosurvival pathways activation, cell cycle promotion and/or cell metabolic alterations. Nonetheless, targeted therapy toward these specific CSC mechanisms is only partially effective to prevent or abolish resistance, suggesting underlying additional causes for CSC resilience. This article aims to provide an integrated picture of the MDR mechanisms that operate in CSCs' behavior and to propose a novel model of tumor evolution during chemotherapy. Targeting the pathways mentioned here might hold promise and reveal new strategies for future clinical therapeutic approaches.

The cancer stem-cell signaling network and resistance to therapy.

The study of cancer stem cells (CSCs) has shown that tumors are driven by a subpopulation of self-renewing CSCs that retain the capacity to engender the various differentiated cell populations that form tumors. The characterization of CSCs has indicated that CSCs are remarkably resistant to conventional radio- and chemo-therapy. Clinically, the remaining populations of CSC are responsible for metastasis and recurrence in patients with cancer, which can lead to the disease becoming chronic and incurable. Therefore, the elimination of CSCs is an important goal of cancer treatments. Furthermore, CSCs are subject to strong regulation by the surrounding microenvironment, which also impacts tumor responses. In this review, we discuss the mechanisms by which pathways that are defective in CSCs influence ultimately therapeutic and clinical outcomes.