Abstract
AZD6244 (ARRY-142886) is an inhibitor of MEK1/2 and can inhibit cell proliferation or induce apoptosis in a cell-type dependent manner. The precise molecular mechanism of AZD6244-induced apoptosis is not clear. To investigate mechanisms of AZD6244 induced apoptosis in human lung cancer, we determined the molecular changes of two subgroups of human lung cancer cell lines that are either sensitive or resistant to AZD6244 treatment. We found that AZD6244 elicited a large increase of Bim proteins and a smaller increase of PUMA and NOXA proteins, and induced cell death in sensitive lung cancer cell lines, but had no effect on other Bcl-2 related proteins in those cell lines. Knockdown of Bim by siRNA greatly increased the IC50 and reduced apoptosis for AZD6244 treated cells. We also found that levels of endogenous p-Thr32-FOXO3a and p-Ser253-FOXO3a were lower in AZD6244-sensitive cells than in AZD6244-resistant cells. In the sensitive cells, AZD6244 induced FOXO3a nuclear translocation required for Bim activation. Moreover, the silencing of FOXO3a by siRNA abrogated AZD6244-induced cell apoptosis. In addition, we found that transfection of constitutively active AKT up-regulated p-Thr32-FOXO3a and p-Ser253-FOXO3a expression and inhibited AZD6244-induced Bim expression in sensitive cells. These results show that Bim plays an important role in AZD6244-induced apoptosis in lung cancer cells and that the PI3K/AKT/FOXO3a pathway is involved in Bim regulation and susceptibility of lung cancer cells to AZD6244. These results have implications in the development of strategies to overcome resistance to MEK inhibitors.
Highlights
Activation of the Ras/Raf/MEK/MAP kinase pathway has been implicated in uncontrolled cell proliferation and tumor growth
Because the balance between antiapoptotic and proapoptotic proteins is critical to drug-induced apoptosis, we evaluated changes in Bcl-2 family proteins in AZD6244 sensitive and resistant lung cancer cell lines and found that the MEK inhibitor AZD6244 up-regulates the proapoptotic BH3-only proteins Bim, p53-upregulated modulator of apoptosis (PUMA) and NOXA, a process associated with subsequent cell death
We found that following sub-G1 cell cycle arrest, 20–40% of AZD6244-sensitive cells underwent apoptosis, but we observed no apoptosis in AZD6244-resistant cells
Summary
Activation of the Ras/Raf/MEK/MAP kinase pathway has been implicated in uncontrolled cell proliferation and tumor growth. AZD6244 (ARRY-142886), a novel, selective, ATP-uncompetitive inhibitor of mitogen-activated protein kinase kinase 1/2 (MEK1/2), has shown activity in nanomolar concentrations against isolated MEK enzyme and numerous cancer cell lines [1]. AZD6244 has shown activity in several tumor xenograft models of human cancer [2,3,4]. Whilst patients from several tumor types have shown responses to MEK inhibitor monotherapy, other patients’ tumors, non-small cell lung cancers, are inherently resistant to MEK inhibition. It is important to understand the underlying mechanisms responsible for resistance to MEK inhibition in the event it becomes important therapeutic modality in this very common cancer
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