Cell Cycle Regulation and Melanoma

Abstract

Dysregulation of cell cycle control is a hallmark of melanomagenesis. Agents targeting the G1-S and G2-M checkpoints, as well as direct anti-mitotic agents, have all shown promising preclinical activity in melanoma. However, in vivo, standalone single agents targeting cell cycle regulation have only demonstrated modest efficacy in unselected patients. The advent of specific CDK 4/6 inhibitors targeting the G1-S transition, with an improved therapeutic index, is a significant step forward. Potential synergy exists with the combination of CDK4/6 inhibitors with existing therapies targeting the MAPK pathway, particularly in subsets of metastatic melanomas such as NRAS and BRAF mutants. This reviews summaries of the latest developments in both preclinical and clinical data with cell cycle-targeted therapies in melanoma.

A New Perspective for Osteosarcoma Therapy: Proteasome Inhibition by MLN9708/2238 Successfully Induces Apoptosis and Cell Cycle Arrest and Attenuates the Invasion Ability of Osteosarcoma Cells in Vitro

“…This discrepancy in phase might be attributable to the enhanced expression of E2F1 and Rb status (Fig. 2C), both of which are key effectors regulating the transition of G1 to S. E2F1 promotes the G1-S transition, whereas Rb inhibits this activity [29]. The Rb-null status of Saos-2 cells appeared to enhance the induction of the G1-S transition by the up-regulation of E2F1 compared with MG-63 cells (Fig.…”

“…When DNA damage occurs, CHK1 can be activated by phosphorylating on serine 345 (S345). Then, p-CHK1 keeps CDC25 being in an inactivated state by phosphorylating it, thus blocks the G2-M transition by keeping CDK1 being in phosphorylation state indirectly; and WEE1 can phosphorylate CDK1 directly at Tyr15 to inhibit the G2-M transition [27,28,29]. Moreover, P53 null cells, which are lacking P53 and exhibited attenuated P21 function, are more reliant on CHK1 and WEE1 to restrain CDK1 in blocking the G2-M transition [30], consistent with our results that MLN2238 treatment caused G2/M arrest accompanied with increased expression of CHK1 and WEE1 in MG-63 cells and, more apparently in Saos-2 cells (Fig.…”

Knockdown of STIM1 expression inhibits non-small-cell lung cancer cell proliferation in vitro and in nude mouse xenografts

“…CDK1 plays a critical role in the transition of cells between the G2 and M phase, as well as the execution of mitosis, and the catalytic activity of CDK1 requires B-type cyclins [40]. CDK1/ cyclin B1 activity appears throughout the G2-M phase, and is turned off by cyclin B1 destruction as cells enter the anaphase of mitosis [41]. CDK2 is a catalytic subunit of the CDK complex, the activity of which is restricted to the G1-S phase of the cell cycle.…”

SHARPIN regulates cell proliferation of cutaneous basal cell carcinoma via inactivation of the transcriptional factors GLI2 and c‑JUN

“…The transition from the G1 phase to S phase is a critical step in determining the rate of cell proliferation, and is modulated by the phosphorylation of retinoblastoma (rb) (54). cdKs are serine/threonine kinases that are regulated by interactions with cyclins and cdK inhibitors, and are the key regulators of the G1-to-S checkpoint (55). after cdK4 binds with its catalytic partner cyclin d to form an active complex, rb is consecutively phosphorylated, thus relieving its inhibition on e2F to allow target genes to promote the G1-to-S phase entry (56).…”