Role of Bcl‑2 on drug resistance in breast cancer polyploidy‑induced spindle poisons

Abstract

Spindle poisons are chemotherapeutic drugs used in the treatment of malignant tumors; however, numerous patients develop resistance following chemotherapy. The present study aimed to induce polyploidy in breast cancer cells using the spindle poison nocodazole to investigate the mechanism of polyploid-induced tumor resistance. It was revealed that the spindle poison nocodazole induced apoptosis in HCC1806 cells but also induced polyploidy in MDA-MB-231 cells. The drug sensitivities of the polyploid MDA-MB-231 cells to paclitaxel, docetaxel, epirubicin, 5-fluorouracil and oxaliplatin were lower than those of the original tumor cells; however, the polyploid MDA-MB-231 cells were more sensitive to etoposide than the original tumor cells. The expression of F-box and WD repeat domain containing 7 (FBW7) was decreased, while the expression of MCL1 apoptosis regulator BCL2 family member (MCL-1) and Bcl-2 was increased, and caspase-3/9 and Bax were not expressed in MDA-MB-231 cells. The resistance to docetaxel and etoposide was reversed, but the sensitivity of paclitaxel was not changed following Bcl-2 silencing. The formation of polyploidy in tumors may be one of the molecular mechanisms underlying tumor resistance to spindle poisons. Expression of the Bcl-2 family members, for example FBW7 and MCL-1, plays a key role in apoptosis and the cell escape process that forms polyploid cells. However, Bcl-2 silencing has different reversal effects on different anti-tumor drugs, which requires further investigation.

Ruxolitinib induces apoptosis of human colorectal cancer cells by downregulating the JAK1/2‑STAT1‑Mcl‑1 axis

“…It was demonstrated that ruxolitinib partly suppressed CRC cell proliferation by inducing apoptosis through activating the intrinsic pathway. Bcl-2 family proteins that are key mediators of the intrinsic apoptosis pathway were screened out ( 25 , 26 ). As shown in Fig.…”

Cisplatin resistant ovarian cancer cells reveal a polyploid phenotype with remarkable activation of nuclear processes

“…As well, the top central genes of the constructed network typically attributed to nuclear process. According to our previous studies indicating the importance of central genes in promotion of cellular phenotype [45,46], we think that the central nodes as well as genes in the densely-connected modules which belonged to chromatid segregation, microtubule polymerization and membrane budding, indicate the key role of nuclear processes and polyploidy in cancer resistance [47][48][49][50][51][52][53][54].…”

Comprehensive review of Bcl‐2 family proteins in cancer apoptosis: Therapeutic strategies and promising updates of natural bioactive compounds and small molecules

“…Dysregulation of these proteins can result from mutations in or upregulation of antiapoptotic genes, leading to resistance to chemotherapy. Numerous studies have indicated that increased expression of Bcl‐2 or an increase in the Bcl‐2/BAX ratio is strongly associated with poor clinical outcomes, rendering cancer cells resistant to chemotherapy and radiation both in vitro and in vivo (Kaloni et al, 2023; Kapoor et al, 2020; Yuan et al, 2020). Patients with Bcl‐2‐positive malignancies are at a higher risk of treatment failure and have a poor prognosis (Makino et al, 2018; Michaud et al, 2009).…”