Obatoclax Induces G1/G0‐Phase Arrest via p38/p21^waf1/Cip1 Signaling Pathway in Human Esophageal Cancer Cells

Abstract

Pan-Bcl-2 family inhibitor obatoclax has been demonstrated to be effective against various cancers, of which the mechanism of action is not fully understood. In this study, we demonstrate that obatoclax suppressed esophageal cancer cell viability with concomitant G1/G0-phase cell cycle arrest. At the tested concentrations (1/2 IC50 and IC50), obatoclax neither induced PARP cleavage nor increased the Annexin V-positive population, suggesting G1/G0-phase arrest rather than apoptosis accounts for most of the reduction of cell viability produced by obatoclax. Double knockdown of Bak and Bax by small interference RNA failed to block obatoclax-induced G1/G0-phase arrest, implying its role in cell cycle progression is Bak/Bax-independent. The cell cycle arresting effect of obatoclax was associated with up-regulation of p21(waf1/Cip1). Knockdown of p21(waf1/Cip1) significantly attenuated obatoclax-induced G1/G0-phase arrest. Although obatoclax stimulated phosphorylation of Erk, p38, and JNK, pharmacological inhibition of p38 but not Erk or JNK blocked obatoclax-induced G1/G0-phase arrest. Moreover, knockdown of p38 abolished the cell cycle arresting effect of obatoclax. In consistent with this finding, inhibition of p38 blocked obatoclax-induced p21(waf1/Cip1) expression while inhibition of Erk or JNK failed to exert similar effect. To conclude, these findings suggest that obatoclax induced cell cycle arrest via p38/p21(waf1/Cip1) signaling pathway. This study may shed a new light on the anti-cancer activity of obatoclax in relation to cell cycle arrest.

Obatoclax and LY3009120 Efficiently Overcome Vemurafenib Resistance in Differentiated Thyroid Cancer

“…8C). This was different from a previous study which reported suppression of esophageal cancer cell viability by Obatoclax with concomitant G1/G0-phase cell cycle arrest 41. Furthermore, while the p-ERK level in the Vemurafenib-resistant K1 cells did not change as the concentration of Vemurafenib increased, it decreased significantly in the LY3009120-treated group (Fig.…”

ABT-263 induces G1/G0-phase arrest, apoptosis and autophagy in human esophageal cancer cells in vitro

“…Although BH3 mimetics are designed to trigger apoptosis, accumulating evidence indicates that their anticancer activity is not limited to the initiation of apoptosis. In addition to their pro-apototic effect, BH3 mimetic agents have been shown to exert anti-proliferative effects by blocking cell cycle progression [31,32] and to induce autophagy in tumor cells, mainly because of the release of Beclin 1 from Bcl-2 and Bcl-xL [20,[33][34][35] . However, the mechanism underlying ABT-263-induced cell cycle arrest and autophagy induction had been unclear.…”

AT‑101 induces G1/G0�phase arrest via the β‑catenin/cyclin�D1 signaling pathway in human esophageal cancer cells

“…Furthermore, AT-101 blocks cell cycle progression by regulating a variety of proteins that mediate G 1 to S phase transition. Of note, our previous studies have demonstrated that other Bcl-2 inhibitors with different chemical structures from AT-101 exhibited a similar pattern on cell cycle progression as well as apoptosis (18,20). Thus, we propose that G 1 /G 0 phase arrest might not be a unique cellular response to AT-101 but instead a common response to Bcl-2 inhibitors, suggesting a potential link between Bcl-2 family members and cell cycle progression.…”

“…There is accumulating evidence showing that the antitumor activity of Bcl-2 inhibitors is not limited to the initiation of apoptosis, despite the fact that Bcl-2 inhibitors were originally designed to induce apoptosis. In this regard, Bcl-2 inhibitors have been reported to block cell cycle progression (18,19), regulate autophagy (20)(21)(22) and inhibit tumor stemness (23). It has been showed that AT-101 significantly suppressed the hedgehog (Hh) signaling pathway and suppressed the growth of Hh-driven cancer in vitro and in vivo (24).…”