Carfilzomib inhibits the growth of lung adenocarcinoma via upregulation of Gadd45a expression

Abstract

Proteasome inhibitors have shown remarkable success in the treatment of hematologic neoplasm. There has been a lot of attention to applying these drugs for solid tumor treatment. Recent preclinical study has signified the effectiveness on cell proliferation inhibition in lung adenocarcinoma treated by carfilzomib (CFZ), a second generation proteasome inhibitor. However, no insight has been gained regarding the mechanism. In this study, we have systematically investigated the CFZ functions in cell proliferation and growth, cell cycle arrest, and apoptosis in lung adenocarcinoma cells. Flow cytometry experiments showed that CFZ significantly induced G2/M cell cycle arrest and apoptosis in lung adenocarcinoma. MTS and colony formation assays revealed that CFZ substantially inhibited survival of lung adenocarcinoma cells. All results were consistently correlated to the upregulation expression of Gadd45a, which is an important gene in modulating cell cycle arrest and apoptosis in response to physiologic and environmental stresses. Here, upregulation of Gadd45a expression was observed after CFZ treatment. Knocking down Gadd45a expression suppressed G2/M arrest and apoptosis in CFZ-treated cells, and reduced cytotoxicity of this drug. The protein expression analysis has further identified that the AKT/FOXO3a pathway is involved in Gadd45a upregulation after CFZ treatment. These findings unveil a novel mechanism of proteasome inhibitor in anti-solid tumor activity, and shed light on novel preferable therapeutic strategy for lung adenocarcinoma. We believe that Gadd45a expression can be a highly promising candidate predictor in evaluating the efficacy of proteasome inhibitors in solid tumor therapy.

Induced resistance to ifosfamide in osteosarcoma cells suggests a more aggressive tumor profile

“…These data corroborate the current study, where only sensitive cells showed positive expression of GADD45A. This gene is responsible for regulating the cell cycle and apoptotic processes in response to physiological and environmental stress, which in OS and other tumors usually show methylation in the CpG region due to epigenetic mechanisms [ 23 , 24 ]. Tumors that lack GADD45A expression have greater angiogenesis and cell migration activity [ 25 ] .…”

A Pan-Cancer Analysis of Transcription Factor Forkhead Box O-3: FOXO3

“…We speculated that FOXO3 seemed to be a tumor suppressor gene in LUAD and FOXO3 alteration in LUAD will destroy its cancer inhibition function. Fang Yang et al had identi ed that car lzomib (CFZ), a second generation proteasome inhibitor, inhibited the growth of LUAD cells through increasing the transactivation of FOXO3 to promote Gadd45a expression [44]. Another report also found that HCQ-induced upregulation and nuclear translocation of FOXO3 was involved in the antitumor effects of HCQ in LUAD cells [45].…”

Carfilzomib activates ER stress and JNK/p38 MAPK signaling to promote apoptosis in hepatocellular carcinoma cells

“…Carfilzomib (CFZ) is a second-generation selective proteasome inhibitor which was approved for the treatment of relapsed or refractory multiple myeloma by the FDA in 2012 and has a significant safety advantage over bortezomib [5] . In addition to hematological malignancies, CFZ also suppresses the growth of solid tumors, such as neuroblastoma, small cell lung cancer, and anaplastic thyroid cancer (ATC) [ 6 – 8 ]. Lee et al .…”