Failure in the balance between kinases and phosphatases activity has been shown in several types of solid cancer, such as colorectal, gastric, liver and breast cancer (BC) ( Martellucci et al., 2020). The uncontrolled activation of kinases and the suppression of phosphatases has been frequently observed in cancer with consequent induction of cell proliferation, migration and survival to anti-cancer therapies. Moreover, oncogenes can influence the balance between kinases and phosphatases activity, causing cell malignant transformation ( Qi et al., 2018). Mutations in kinases ( Irby et al., 1999 Zhang et al., 2009) or phosphatases ( Stebbing et al., 2014 Zhao et al., 2015) that lead to either a loss-of-function or gain-of-function are likely to cause cancer. The main role of kinases and phosphatases is to regulate post-translational modifications of proteins, which are essential to govern cellular signaling networks ( Sacco et al., 2012). Moreover, we discuss the potential of inhibitors of these proteins in counteracting CSCs expansion during cancer development and progression. Here, we provide a comprehensive overview of the major protein kinases and phosphatases pathways by which CSCs can evade normal physiological constraints on survival, growth, and invasion. Notwithstanding the role of kinases and phosphatases in cancer has been widely investigated, their aberrant activation in the compartment of CSCs is nowadays being explored as new potential Achille’s heel to strike. Therefore, alterations in kinases and phosphatases functionality is a hallmark of cancer. These proteins are crucial regulators of intracellular signaling pathways mediating multiple cellular activities. Kinases and phosphatases are implicated in many cellular processes, such as proliferation, differentiation and oncogenic transformation. Standard anti-cancer treatments are not always conclusively curative, posing an urgent need to discover new targets for an effective therapy. Accumulating evidence have highlighted the relevance of a small population of cancer cells, named cancer stem cells (CSCs), in the resistance to therapies, as well as cancer recurrence and metastasis. Metastatic disease represents the major cause of death in oncologic patients worldwide. 5Azienda Ospedaliera Universitaria Policlinico (AOUP), Palermo, Italy.4Villa Sofia-Cervello Hospital, Palermo, Italy. 3Department of Experimental Oncology, Mediterranean Institute of Oncology (IOM), Catania, Italy.2Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, Palermo, Italy.1Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy.Alice Turdo 1 Caterina D’Accardo 1 Antonino Glaviano 2 Gaetana Porcelli 1 Cristina Colarossi 3 Lorenzo Colarossi 3 Marzia Mare 3 Naida Faldetta 4 Chiara Modica 2 Giuseppe Pistone 1 Maria Rita Bongiorno 1 Matilde Todaro 1,5 Giorgio Stassi 2*
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