Potential Role of ASC, a Proapoptotic Protein, for Determining the Cisplatin Susceptibility of Lung Cancer Cells

Abstract

Primary lung cancer is the most frequent cause of cancer-related deaths worldwide. Cisplatin has been used as a key drug in the treatment for patients with lung cancer; however, most of the patients failed to respond to cisplatin within several months, and the mechanisms underlying the cisplatin resistance have not been fully elucidated. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor protein in the formation of inflammasomes. ASC is also involved in apoptotic signaling. Importantly, ASC expression is decreased in lung cancer and various cancers, but its precise function in tumor progression remains unknown. To explore the hitherto unknown role of ASC in lung cancer, we initially searched for lung cancer cell lines with higher expression levels of ASC using Cancer Cell Line Encyclopedia (CCLE) database, thereby identifying the A549 human non-small cell lung cancer cell line. Accordingly, with retroviral shRNA, the expression of ASC was forced to decrease in A549 cells. Stable ASC-knockdown cells, thus established, showed the increased activities of proliferation, motility, and invasion, compared with control cells. Importantly, ASC-knockdown cells also became resistant to cisplatin, but not to other anti-cancer agents, 5-fluorouracil and paclitaxel. Bcl-2 and phospho-Src levels were increased in ASC-knockdown cells. A Bcl-2 inhibitor, ABT-199, induced an apoptotic response in ASC-knockdown cells, and dasatinib, a Src inhibitor, blocked cell invasiveness. Thus, ASC may be involved in tumor suppression and cell death via Bcl-2 and pSrc. Targeting Bcl-2 and Src in ASC-downregulated populations of lung cancer may improve treatment outcome.

RETRACTED ARTICLE: Anti-inflammatory effect of up-regulated microRNA-221-3p on coronary heart disease via suppressing NLRP3/ASC/pro-caspase-1 inflammasome pathway activation

“…A study has revealed that the activation of NLRP3 inflammasome participates in CHD progress, and down-regulating NLRP3 and its downstream mediators can suppress the inflammatory process of atherosclerosis [13]. ASC is an important adaptor protein in the formation of inflammasomes [14]. There is a study reporting a neuromodulatory effect of NLRP3 and ASC on neonatal hypoxic-ischemic encephalopathy [15].…”

Pyroptosis: shedding light on the mechanisms and links with cancers

“…In previous studies, various pyroptosis pathway members, including but not limited to inflammasomes, gasdermins, and various inflammatory cytokines, have been reported to participate in the genesis, proliferation, metastasis, and invasion of pulmonary cancer (63)(64)(65). Depending on the specific contexts, these components play diverse and even sometimes opposing roles in tumor promotion and therapeutic processes.…”

The Multifaceted Roles of Pyroptotic Cell Death Pathways in Cancer

“…ASC negatively modulated the tumorigenesis of fibrosarcoma by activating caspase-9 and inhibiting the nuclear factor-ĸB (NF-ĸB)-related X-linked inhibitor of apoptosis protein (XIAP) [104]. ASC inhibited the proliferation, motility and invasion of lung cancer cells through downregulation of Bcl-2 and phospho-Src [105]. It has been reported that the apoptosis sponsor caspase-8 also functions as an enhancer of cancer cell migration by phosphorylation via Src [106].…”