Pharmacological inhibition of the SKP2/p300 signaling axis restricts castration-resistant prostate cancer.

SKP2, an F-box protein of the SCF type of the E3 ubiquitin ligase complex, plays an important function in driving tumorigenesis through the destruction of numerous tumor-suppressive proteins. Besides its critical role in cell cycle regulation, proto-oncogenic functions of SKP2 have also been shown in a cell cycle regulation-independent manner. Therefore, uncovering novel physiological upstream regulators of SKP2 signaling pathways would be essential to retard aggressive malignancies. Here, we report that elevation of SKP2 and EP300 transcriptomic expression is a hallmark of castration-resistant prostate cancer. We also found that SKP2 acetylation is likely a critical driven event in castration-resistant prostate cancer cells. Mechanistically, SKP2-acetylation is mediated by the p300 acetyltransferase enzyme for post-translational modification (PTM) event that is induced upon stimulation with dihydrotestosterone (DHT) in prostate cancer cells. Moreover, ectopic expression of acetylation-mimetic K68/71Q mutant of SKP2 in LNCaP cells could confer resistance to androgen withdrawal-induced growth arrest and promotes prostate cancer stem cell (CSC)-like traits including survival, proliferation, stemness formation, lactate production, migration, and invasion. Furthermore, inhibition of p300-mediated SKP2 acetylation or SKP2-mediated p27-degradation by pharmacological inhibition of p300 or SKP2 could attenuate epithelial-mesenchymal transition (EMT) and the proto-oncogenic activities of the SKP2/p300 and androgen receptor (AR) signaling pathways. Therefore, our study identifies the SKP2/p300 axis as a possible molecular mechanism driving castration-resistant prostate cancers, which provides pharmaceutical insight into inactivation of the SKP2/p300 axis for restriction of CSC-like properties, thereby benefiting clinical diagnosis and cancer therapy.

CAR T-Cell Therapy for Patients with Multiple Myeloma: Current Evidence and Challenges.

The therapeutic landscape of multiple myeloma (MM) has benefited from an emergence of novel therapies over the last decade. By inducing T-cell kill of target cancer cells, chimeric antigen receptor (CAR) T-cell therapies have improved outcomes of patients with hematologic malignancies. B-cell maturation antigen (BCMA) is the current target antigen of choice for most CAR T-cell products under investigation for MM. However, their shortcomings deal with logistical and clinical challenges, including limited availability, manufacturing times, and toxicities. This article provides an overview of recently developed and investigational CAR T-cell therapies for MM, highlighting current evidence and challenges.

ATM: Main Features, Signaling Pathways, and Its Diverse Roles in DNA Damage Response, Tumor Suppression, and Cancer Development.

ATM is among of the most critical initiators and coordinators of the DNA-damage response. ATM canonical and non-canonical signaling pathways involve hundreds of downstream targets that control many important cellular processes such as DNA damage repair, apoptosis, cell cycle arrest, metabolism, proliferation, oxidative sensing, among others. Of note, ATM is often considered a major tumor suppressor because of its ability to induce apoptosis and cell cycle arrest. However, in some advanced stage tumor cells, ATM signaling is increased and confers remarkable advantages for cancer cell survival, resistance to radiation and chemotherapy, biosynthesis, proliferation, and metastasis. This review focuses on addressing major characteristics, signaling pathways and especially the diverse roles of ATM in cellular homeostasis and cancer development.

COP9 signalosome subunit 6 (CSN6) regulates E6AP/UBE3A in cervical cancer.

Cervical cancer is one of the leading causes of cancer death in women. Human papillomaviruses (HPVs) are the major cause in almost 99.7% of cervical cancer. E6 oncoprotein of HPV and E6-associated protein (E6AP) are critical in causing p53 degradation and malignancy. Understanding the E6AP regulation is critical to develop treating strategy for cervical cancer patients. The COP9 signalosome subunit 6 (CSN6) is involved in ubiquitin-mediated protein degradation. We found that both CSN6 and E6AP are overexpressed in cervical cancer. We characterized that CSN6 associated with E6AP and stabilized E6AP expression by reducing E6AP poly-ubiquitination, thereby regulating p53 activity in cell proliferation and apoptosis. Mechanistic studies revealed that CSN6-E6AP axis can be regulated by EGF/Akt signaling. Furthermore, inhibition of CSN6-E6AP axis hinders cervical cancer growth in mice. Taken together, our results indicate that CSN6 is a positive regulator of E6AP and is important for cervical cancer development.

Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies.

Cancer cells are well documented to rewire their metabolism and energy production networks to support and enable rapid proliferation, continuous growth, survival in harsh conditions, invasion, metastasis, and resistance to cancer treatments. Since Dr. Otto Warburg's discovery about altered cancer cell metabolism in 1930, thousands of studies have shed light on various aspects of cancer metabolism with a common goal to find new ways for effectively eliminating tumor cells by targeting their energy metabolism. This review highlights the importance of the main features of cancer metabolism, summarizes recent remarkable advances in this field, and points out the potentials to translate these scientific findings into life-saving diagnosis and therapies to help cancer patients.