c‐Rel is a cell cycle modulator in human melanoma cells

Abstract

Melanoma progression and resistance to therapy are associated with faulty regulation of signalling molecules including the central transcription factor NF‐κB. Increased expression of the c‐Rel subunit of NF‐κB has been described in progressing melanoma, though mechanistic implications of this upregulation remain unclear. To elucidate the functional role of c‐Rel in melanoma biology, we have assessed its expression in human melanoma as well as in melanoma cell lines. Suppression of c‐Rel expression in four melanoma cell lines resulted in reduced growth and altered cell cycle regulation, namely G2/M and polyploid phase induction. Moreover, mitotic spindle morphology was profoundly altered in three of the cell lines with a predominance of monopolar structures. These findings suggest that c‐Rel is involved in G2/M phase regulation, prevention of polyploidy and, consequently, chromosomal stability. Our results highlight a novel tumor‐promoting function of c‐Rel in human melanoma cells through governing cell cycle regulation.

Beta3-Tubulin Is Critical for Microtubule Dynamics, Cell Cycle Regulation, and Spontaneous Release of Microvesicles in Human Malignant Melanoma Cells (A375)

“…Such data provide direct evidence that β3-tubulin alters melanoma cell cycle regulation. G2/M arrest, which may be the result of defective mitotic spindle formation, was shown to enhance the cytotoxic effect of chemotherapy in melanoma cell lines [29,30]. These results are consistent with previous work on Hela cells [31], where the reduction of β3-tubulin expression by siRNA resulted in partial inhibition of cell growth.…”

New insights into the Lck-NF-κB signaling pathway

“…NF-κB functions as an anti-apoptotic molecule through activating the transcription of related genes, such as activating endogenous inhibitors of apoptosis [apoptosis protein1 (IAP1), IAP2, TRAF1 and TRAF2, B-cell lymphoma-2 (BCL2) family of proteins like BCL2 and BCL-X L ] that block both death receptor-mediated apoptosis and mitochondrial pathways. The NF-κB subunit c-Rel was found to be preferentially expressed in myeloid cells and lymphocytes; c-Rel deletion in myeloid cells specifically abolished tumor growth in mice injected with lymphoma cell lines, reduced cell proliferation, and altered cell cycle progression in human melanoma cell lines (Priebe et al, 2019;Li et al, 2020). c-Rel inhibition blocked human myeloid-derived suppressor cell expansion, which was markedly increased in patients with chronic inflammation or cancer (Bronte et al, 2016;Kumar et al, 2016).…”

Emerging Strategies to Attack Polyploid Cancer Cells

“…For example, loss-of-function mutations in tumor suppressors such as BRCA2 [4], TP53 [5] and APC [6], all increase the rate of cytokinetic failure, while activating kinase mutations can impact the fidelity of mitosis. Signaling cascades converge to influence the biogenesis and function of centrosomes, the integrity of the mitotic spindle assembly checkpoint (SAC), and the completion of cytokinesis [7][8][9]. The SAC acts as a safeguard for the accurate segregation of chromosomes, ensuring proper attachment of kinetochores to microtubules of the mitotic spindle and optimal tension between bi-oriented sister kinetochores before the transition to anaphase (for review see [10][11][12]).…”