Survivin knockdown induces senescence in TTF‑1-expressing, KRAS-mutant lung adenocarcinomas

Abstract

Survivin plays a key role in regulating the cell cycle and apoptosis, and is highly expressed in the majority of malignant tumors. However, little is known about the roles of survivin in KRAS-mutant lung adenocarcinomas. In the present study, we examined 28 KRAS-mutant lung adenocarcinoma tissues and two KRAS-mutant lung adenocarcinoma cell lines, H358 and H441, in order to elucidate the potential of survivin as a therapeutic target. We found that 19 (68%) of the 28 KRAS-mutant lung adenocarcinomas were differentiated tumors expressing thyroid transcription factor-1 (TTF-1) and E-cadherin. Patients with tumors immunohistochemically positive for survivin (n=18) had poorer outcomes than those with survivin-negative tumors (n=10). In the H358 and H441 cells, which expressed TTF-1 and E-cadherin, survivin knockdown alone induced senescence, not apoptosis. However, in monolayer culture, the H358 cells and H441 cells in which survivin was silenced, underwent significant apoptosis following combined treatment with ABT-263, a Bcl-2 inhibitor, and trametinib, a MEK inhibitor. Importantly, the triple combination of survivin knockdown with ABT-263 and trametinib treatment, clearly induced cell death in a three-dimensional cell culture model and in an in vivo tumor xenograft model. We also observed that the growth of the H358 and H441 cells was slightly, yet significantly suppressed in vitro when TTF-1 was silenced. These findings collectively suggest that the triple combination of survivin knockdown with ABT-263 and trametinib treatment, may be a potential strategy for the treatment of KRAS-mutant lung adenocarcinoma. Furthermore, our findings indicate that the well-differentiated type of KRAS-mutant lung tumors depends, at least in part, on TTF-1 for growth.

Analysis of the clinicopathological characteristics, genetic phenotypes, and prognostic of pure mucinous adenocarcinoma

“…Shanzhi et al found that the levels of TTF‐1 expression may guide clinical therapy for LUAD with EGFR mutations . Moreover, in a previous study, lung adenocarcinoma with KRAS mutation has been found to depend on TTF‐1 expression for growth and to possibly be regulated by survivin protein . More studies are needed to elucidate the role of TTF‐1 in the process of PMA.…”

Combination of Niraparib, Cisplatin and Twist Knockdown in Cisplatin-Resistant Ovarian Cancer Cells Potentially Enhances Synthetic Lethality through ER-Stress Mediated Mitochondrial Apoptosis Pathway

“…The 3D cell culture aims at recapitulating in vivo tissue architectures to provide physiologically relevant models to study normal development and disease [ 74 , 75 ]. Alt-hough the 3D culture model cannot fully recapitulate all aspects of the in vivo environment, it offers more benefits than a 2D culture.…”

Propionate of a microbiota metabolite induces cell apoptosis and cell cycle arrest in lung cancer

“…Survivin, an antiapoptotic protein, is overexpressed in several types of cancer, and knockdown of Survivin induces cell apoptosis by increasing Bad and Bax expression and inducing G2/M arrest (6). Additionally, in an in vivo xenograft model of KRAS-mutant lung adenocarcinoma, Survivin knockdown and trametinib treatment induced cell death (7). Moreover, in hepatocellular carcinoma cells, treatment with ATB-263, a novel Bcl-2 inhibitor, and silencing of Survivin induced cell apoptosis; these results implied that Survivin knockdown is an important method to overcome the hurdle of drug resistance in cancer therapy (8), and the development of a method for silencing Survivin is urgently needed.…”