CNOT2 Is Critically Involved in Atorvastatin Induced Apoptotic and Autophagic Cell Death in Non-Small Cell Lung Cancers

Abstract

Though Atorvastatin has been used as a hypolipidemic agent, its anticancer mechanisms for repurposing are not fully understood so far. Thus, in the current study, its apoptotic and autophagic mechanisms were investigated in non-small cell lung cancers (NSCLCs). Atorvastatin increased cytotoxicity, sub G1 population, the number of apoptotic bodies, cleaved poly (ADP-ribose) polymerase (PARP) and caspase 3 and activated p53 in H1299, H596, and H460 cells. Notably, Atorvastatin inhibited the expression of c-Myc and induced ribosomal protein L5 and L11, but depletion of L5 reduced PARP cleavages induced by Atorvastatin rather than L11 in H1299 cells. Also, Atorvastatin increased autophagy microtubule-associated protein 1A/1B-light chain 3II (LC3 II) conversion, p62/sequestosome 1 (SQSTM1) accumulation with increased number of LC3II puncta in H1299 cells. However, late stage autophagy inhibitor chloroquine (CQ) increased cytotoxicity in Atorvastatin treated H1299 cells compared to early stage autophagy inhibitor 3-methyladenine (3-MA). Furthermore, autophagic flux assay using RFP-GFP-LC3 constructs and Lysotracker Red or acridine orange-staining demonstrated that autophagosome-lysosome fusion is blocked by Atorvastatin treatment in H1299 cells. Conversely, overexpression of CCR4-NOT transcription complex subunit 2(CNOT2) weakly reversed the ability of Atorvastatin to increase cytotoxicity, sub G1 population, cleavages of PARP and caspase 3, LC3II conversion and p62/SQSTM1 accumulation in H1299 cells. In contrast, CNOT2 depletion enhanced cleavages of PARP and caspase 3, LC3 conversion and p62/SQSTM1 accumulation in Atorvastatin treated H1299 cells. Overall, these findings suggest that CNOT2 signaling is critically involved in Atorvastatin induced apoptotic and autophagic cell death in NSCLCs.

Colocalization of MID1IP1 and c-Myc is Critically Involved in Liver Cancer Growth via Regulation of Ribosomal Protein L5 and L11 and CNOT2

“…Emerging evidence reveals that CNOT2 acts as an oncogene [22,23], adipogenic molecule [21] and autophagy regulator [22,38]. Considering that nonalcoholic fatty liver disease (NAFLD) increases the risk of HCC progression [39], and obesity-like condition promotes the proliferation of breast cancer via Warburg effect inversion [40], hyperlipidemic or adipogenic molecules may be similarly involved in cancer progression.…”

Autophagy-related signaling pathways are involved in cancer (Review)

“…A number of autophagy regulators, including everolimus tablets, venezuela, AT-101, rapamycin, 3-MA, LY294002, bafilomycin A1, autophinib, ROC-325, IITZ-01, daurisoline, 3BDO, 9f, chloroquine (CQ), hydroxychloroquine (HCQ) and spautin-1, are used to treat cancer (103)(104)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114)(115)(116)(117). CQ and HCQ are lysosome inhibitors that inhibit autophagy and induce the accumulation of autophagosomes by altering lysosomal pH (110,117).…”

Diverse functions of deadenylases in DNA damage response and genomic integrity

“…CNOT3 is proposed to contribute to the resistance to cisplatin of lung cancer cells (Jing et al, 2019) and may target CDKN1A/p21 in nonsmall cell lung cancer (Shirai et al, 2019). CNO2 is hypothesized to be involved in Atorvastatin‐induced cell death of nonsmall cell lung cancers (J. Lee et al, 2019). However, the impacts of the CCR4‐Not complex in carcinogenesis is a largely unexploded field and further research is needed to clarify whether the CCR4‐Not complex contributes to the proliferation of the genomically instable cancer cells.…”