Cabazitaxel-induced autophagy via the PI3K/Akt/mTOR pathway contributes to A549 cell death

Abstract

Cabazitaxel has been used to treat castration-resistant prostate cancer since its approval by the US Food and Drug Administration in 2010. However, whether cabazitaxel may inhibit the proliferation of other tissue-derived cancer cells, and its underlying mechanism, remains unknown. In the present study, the A549 lung adenocarcinoma cancer cell line was exposed to cabazitaxel, in order to investigate its cytotoxic effect and determine the underlying mechanism. The results demonstrated that cabazitaxel was able to induce autophagy in A549 cells, as evidenced by the formation of autophagosomes, upregulated LC3-II expression and increased LC3 puncta. Cabazitaxel-induced autophagy had a cytotoxic effect on A549 cells, as evidenced by the induction of cell death and cell cycle arrest at G2/M phase, which was independent of the apoptotic pathway. Furthermore, transfection with Beclin1 small interfering RNA and treatment with the autophagy inhibitor 3-methyladenine protected cells from cabazitaxel-induced cell death, thus confirming that cabazitaxel-induced autophagy contributed to A549 cell death. In addition, cabazitaxel targeted the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway to induce autophagy, as indicated by reduced phosphorylation of Akt and mTOR. In conclusion, the present study demonstrated that cabazitaxel exerts a cytotoxic effect on A549 cells by acting on the PI3K/Akt/mTOR pathway to promote autophagic cell death. This result supports the potential use of cabazitaxel as a chemotherapeutic agent for the treatment of lung cancer.

Autophagy-dependent cell death – where, how and why a cell eats itself to death

“…We refer the reader to a thorough review that has highlighted many studies showing ADCD by various agents in different cancer cell types, such as the BH3 mimetics obatoclax and gossypol, histone deacetylase inhibitors, as well as the natural plant products resveratrol and betulinic acid (Fulda and Kögel, 2015). Additionally, more recent studies that have clearly demonstrated autophagy gene-dependent cell death in the absence of apoptosis include the treatment of glioma cells with a combination of the tricyclic antidepressant imipramine (IM) and the anti-platelet drug ticlopidine (TIC; an inhibitor of ADP receptor P2Y 12 ) (Shchors et al, 2015), the treatment of lung carcinoma cells with cabazitaxel (Huo et al, 2016) and the treatment of hepatocellular carcinoma with the natural flavonoid kaempferol (Han et al, 2017). Importantly, ADCD triggered by IM and TIC has also been associated with slower tumor progression and improved survival in in vivo mouse glioma models; knockdown of Atg7 in the glioma cells attenuates the effects of the drugs on survival and tumor growth (Shchors et al, 2015).…”

TEEG Induced A549 Cell Autophagy by Regulating the PI3K/AKT/mTOR Signaling Pathway

“…As a member of the PI3K-related kinase family, mTOR is associated with cell proliferation and cell metabolism. Previous studies have shown that inhibition of AKT and its downstream target mTOR contributes to the initiation of autophagy [35]. Meanwhile, mTOR is an important downstream target of PI3K/AKT and positively regulates p70S6K; PI3K/AKT/mTOR is an important intracellular signaling pathway in regulating cell survival and death.…”

Autophagy and Cell Death: Antitumor Drugs Targeting Autophagy

“…A novel hybrid of the 3-benzyl coumarin seco-B-ring derivative and phenylsulfonylfuroxan (compound 6) reduces the phosphorylation levels of mTOR-S2448, Akt-S373, and the downstream p70s6K-S371 and 4EBP1-pT45 proteins in a concentration-/time-dependent manner to induce autophagy and apoptosis of A549 cells [56]. The antiprostate-cancer drug, cabazitaxel, also inhibits proliferation of A549 cells through autophagy which is regulated by the PI3K/Akt/mTOR pathway [57]. Ophiopogon japonicus is a traditional medicinal plant, and its main components are flavonoids and steroidal saponins.…”