Activation of the p38 MAPK/Akt/ERK1/2 signal pathways is required for the protein stabilization of CDC6 and cyclin D1 in low‐dose arsenite‐induced cell proliferation

Abstract

Arsenic trioxide (ATO) is a first-line anti-cancer agent for acute promyelocytic leukemia, and induces apoptosis in other solid cancer cell lines including breast cancer cells. However, as with arsenites found in drinking water and used as raw materials for wood preservatives, insecticides, and herbicides, low doses of ATO can induce carcinogenesis after long-term exposure. At 24 h after exposure, ATO (0.01-1 µM) significantly increased cell proliferation and promoted cell cycle progression from the G1 to S/G2 phases in the non-tumorigenic MCF10A breast epithelial cell line. The expression of 14 out of 96 cell-cycle-associated genes significantly increased, and seven of these genes including cell division cycle 6 (CDC6) and cyclin D1 (CCND1) were closely related to cell cycle progression from G1 to S phase. Low-dose ATO steadily increased gene transcript and protein levels of both CDC6 and cyclin D1 in a dose- and time-dependent manner. Low-dose ATO produced reactive oxygen species (ROS), and activated the p38 MAPK, Akt, and ERK1/2 pathways at different time points within 60 min. Small molecular inhibitors and siRNAs inhibiting the activation of p38 MAPK, Akt, and ERK1/2 decreased the ATO-increased expression of CDC6 protein. Inhibiting the activation of Akt and ERK1/2, but not p38 MAPK, decreased the ATO-induced expression of cyclin D1 protein. This study reports for the first time that p38 MAPK/Akt/ERK1/2 activation is required for the protein stabilization of CDC6 in addition to cyclin D1 in ATO-induced cell proliferation and cell cycle modulation from G1 to S phase.

PML/RARα-Regulated miR-181a/b Cluster Targets the Tumor Suppressor RASSF1A in Acute Promyelocytic Leukemia

“…Finally, in contrast to ATRA, arsenic trioxide which induces apoptosis in APL does not affect miR-181a/b expression and RASSF1A protein. This correlates with the finding that arsenic trioxide does not donwregulate cyclin D1 protein (50). Based on these findings, we claim RASSF1A as an important factor in the granulocytic differentiation, which prevents cyclin D1 accumulation, cell cycle progress and promotes differentiation upon ATRA-treatment in APL blasts.…”

Systematic dissection of dysregulated transcription factor–miRNA feed-forward loops across tumor types

“…In the identified pan-cancer FFLs, CCND1 and JUN are drug targets of ATO, which span three pan-cancer FFLs (Figure 6). ATO is an antagonist of CCND1, which has been validated in many cancers, such as bladder cancer [62], breast cancer [63], kidney cancer [64], liver cancer [65] and NSCLC [66]. In this study, we found that CCND1 was upregulated in most of the tumor types (Figure 6).…”

Neuroglobin Plays a Protective Role in Arsenite-Induced Cytotoxicity by Inhibition of Cdc42 and Rac1GTPases in Rat Cerebellar Granule Neurons

“…Apoptosis is induced through many ways including the disequilibrium of apoptotic/anti-apoptotic BCL 2 family members [43], reactive oxidative species generation [44], cytochrome C release, loss of mitochondrial transmembrane potential, inactivation of NF-kB [45,46], activation of caspases [47], activation of MAPK pathways [48,49], as well as activation of Rho GTPases pathway [9]. Among these mechanisms, the two best-characterized Rho family members Cdc42 and Rac1, have been found to play a critical role in regulating cellular processes, including cell proliferation, migration, differentiation, and apoptosis [11,50].…”