Dataset Information

The effect of paclitaxel on apoptosis, autophagy and mitotic catastrophe in AGS cells.

ABSTRACT: Paclitaxel is an anti-microtubule agent that has been shown to induce cell death in gastric cancer. However, the detailed mechanism of action is unclear. In this study, we reveal that the paclitaxel-induced cell death mechanism involves mitotic catastrophe, autophagy and apoptosis in AGS cells. Paclitaxel induced intrinsic apoptosis by activating caspase-3, caspase-9 and PARP. In addition, the significant increase in autophagy marker LC3B-II, together with Atg5, class III PI3K and Beclin-1, and the down-regulation of p62 following paclitaxel treatment verified that paclitaxel induced autophagy. Further experiments showed that paclitaxel caused mitotic catastrophe, cell cycle arrest of the accumulated multinucleated giant cells at the G2/M phase and induction of cell death in 24 h. Within 48 h, the arrested multinucleated cells escaped mitosis by decreasing cell division regulatory proteins and triggered cell death. Cells treated with paclitaxel for 48 h were grown in fresh medium for 24 h and checked for CDC2, CDC25C and lamin B1 protein expressions. These proteins had decreased significantly, indicating that the remaining cells became senescent. In conclusion, it is suggested that paclitaxel-induced mitotic catastrophe is an integral part of the cell death mechanism, in addition to apoptosis and autophagy, in AGS cells.

SUBMITTER: Khing TM

PROVIDER: S-EPMC8648765 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The effect of paclitaxel on apoptosis, autophagy and mitotic catastrophe in AGS cells.

Khing Tin Myo TM Choi Won Seok WS Kim Dong Min DM Po Wah Wah WW Thein Wynn W Shin Chang Yell CY Sohn Uy Dong UD

Scientific reports 20211206 1

Paclitaxel is an anti-microtubule agent that has been shown to induce cell death in gastric cancer. However, the detailed mechanism of action is unclear. In this study, we reveal that the paclitaxel-induced cell death mechanism involves mitotic catastrophe, autophagy and apoptosis in AGS cells. Paclitaxel induced intrinsic apoptosis by activating caspase-3, caspase-9 and PARP. In addition, the significant increase in autophagy marker LC3B-II, together with Atg5, class III PI3K and Beclin-1, and ...[more]

PMID: 34873207

Similar Datasets

Project description:Paclitaxel plays a major role in the treatment of ovarian cancer; however, resistance to paclitaxel is frequently observed. Thus, new therapy that can overcome paclitaxel resistance will be of significant clinical importance. We evaluated antiproliferative effects of an antimitotic and antivascular agent BPR0L075 in paclitaxel-resistant ovarian cancer cells. BPR0L075 displays potent and broad-spectrum cytotoxicity at low nanomolar concentrations (IC50 = 2-7 nM) against both parental ovarian cancer cells (OVCAR-3, SKOV-3, and A2780-1A9) and paclitaxel-resistant sublines (OVCAR-3-TR, SKOV-3-TR, 1A9-PTX10), regardless of the expression levels of the multidrug resistance transporter P-gp and class III β-tubulin or mutation of β-tubulin. BPR0L075 blocks cell cycle at the G2/M phase in paclitaxel-resistant cells while equal concentration of paclitaxel treatment was ineffective. BPR0L075 induces cell death by a dual mechanism in parental and paclitaxel-resistant ovarian cancer cells. In the parental cells (OVCAR-3 and SKOV-3), BPR0L075 induced apoptosis, evidenced by poly(ADP-ribose) polymerase (PARP) cleavage and DNA ladder formation. BPR0L075 induced cell death in paclitaxel-resistant ovarian cancer cells (OVCAR-3-TR and SKOV-3-TR) is primarily due to mitotic catastrophe, evidenced by formation of giant, multinucleated cells and absence of PARP cleavage. Immunoblotting analysis shows that BPR0L075 treatment induced up-regulation of cyclin B1, BubR1, MPM-2, and survivin protein levels and Bcl-XL phosphorylation in parental cells; however, in resistant cells, the endogenous expressions of BubR1 and survivin were depleted, BPR0L075 treatment failed to induce MPM-2 expression and phosphorylation of Bcl-XL. BPR0L075 induced cell death in both parental and paclitaxel-resistant ovarian cancer cells proceed through caspase-3 independent mechanisms. In conclusion, BPR0L075 displays potent cytotoxic effects in ovarian cancer cells with a potential to overcome paclitaxel resistance by bypassing efflux transporters and inducing mitotic catastrophe. BPR0L075 represents a novel microtubule therapeutic to overcome multidrug resistance and trigger alternative cell death by mitotic catastrophe in ovarian cancer cells that are apoptosis-resistant.

Project description:BackgroundGastric cancer is one of the most common malignant tumors in the world. Albumin paclitaxel (Nab-PTX) is a novel microtubule inhibitor with albumin as the carrier. Several clinical trials are underway in gastric cancer, but the autophagy mechanism of Nab-PTX on gastric cancer is still unclear. The autophagy and apoptosis effects of Nab-PTX compared with 5-pentafluorouracil (5-Fu) and lobaplatin (LBP) in gastric cancer are also unclear.ObjectiveThis article will compare the effects of Nab-PTX, 5-Fu, LBP, and albumin paclitaxel + 5-pentafluorouracil (Nab-PTX + 5-Fu) on AGS cells from the perspective of autophagy and apoptosis, which is to provide new ideas and experimental evidence for gastric cancer.Method(1) Experimental groups were control (Ctrl), Nab-PTX, 5-Fu, LBP, and Nab-PTX + 5-Fu. (2) CCK-8 assay was used to reflect cell viability and proliferation. (3) The flow cytometry was used to perform the 24-hour apoptosis and cell cycle of each group. (4) Western blot assay was used to investigate autophagy signal proteins LC3I/LC3II, LC3II/LC3I, SQSTM1/p62, Beclin-1, Atg12, Atg5, p-mULK1, p-AMPK, p-mTOR, and apoptosis signal proteins Bax and Bcl-2.ResultsNab-PTX, 5-Fu, LBP, and Nab-PTX + 5-Fu inhibited AGS cells' proliferation and arrested the cell cycle. At the same time, each group increased the apoptosis of AGS cells to various degrees (Nab-PTX + 5-Fu > Nab-PTX > 5-Fu > LBP, respectively). The experimental results showed that Nab-PTX and Nab-PTX + 5-Fu promoted autophagy and apoptosis of AGS cells. The comparison of Nab-PTX, 5-Fu, and LBP between groups revealed that 5-Fu inhibited autophagy and the expression of apoptosis protein Bax. In LBP, abnormal activation of autophagy downstream, blocking of autophagy flow, abnormal increase of ATG12, and increased expression of apoptosis protein Bax occurred. Further study found that the autophagy upstream mechanism is different.ConclusionNab-PTX, 5-Fu, LBP, and Nab-PTX + 5-Fu can inhibit cell proliferation, promote cell apoptosis, and induce the difference in autophagy expression. The autophagy difference of this antitumor drug may be related to its inducing apoptosis. Meanwhile, Nab-PTX has a better antitumor effect than 5-Fu and LBP in gastric cancer, and the combination of Nab-PTX + 5-Fu has more antitumor advantages.

Dataset Information

The effect of paclitaxel on apoptosis, autophagy and mitotic catastrophe in AGS cells.

Publications

The effect of paclitaxel on apoptosis, autophagy and mitotic catastrophe in AGS cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets