Mad2 and BubR1: chemotherapeutic coordinators in gastric cancer

This article refers to:

Mad2 and BubR1 modulates tumourigenesis and paclitaxel response in MKN45 gastric cancer cells

Gastric cancer (GC) is the fourth most common cancer worldwide and occurs most frequently in East Asia and Eastern Europe.¹ If the GC is resectable, surgery can be selected as the initial treatment. On the other hand, chemotherapy or adjuvant chemotherapy is required in cases with unresectable or recurrent cancers, respectively. A previous clinical study demonstrated that treatment with trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2), in combination with chemotherapy can be efficacious for patients with HER2-positive advanced GC.² On the other hand, paclitaxel and docetaxel, which are mainstays in cancer chemotherapy targeting microtubule dynamics, are widely used in the treatment of GC as part of combination chemotherapy with other agents, such as 5-fluorouracil (5-FU), S-1, and cisplatin, because no more than 22.1% of GCs are HER2-positive.^2,3 Microtubule-targeting drugs, including paclitaxel and docetaxel, suppress spindle microtubule depolymerization and consequently the spindle assembly checkpoint (SAC) is not satisfied, which is a central mechanism underlying an extended mitotic arrest that can lead to cell death. The activity of Mad2 or BubR1, a key component of the SAC, is involved in paclitaxel sensitivity.^4,5

The article by Bargiela-Iparraguirre et al.⁶ in this issue of Cell Cycle shows that Mad2 and BubR1 are markedly overexpressed in GC cell lines. They further demonstrate that downregulation of the expression levels of Mad2 and BubR1 modulates the proliferation, migration, and invasion of GC cells, suggesting that high expression levels of Mad2 and BubR1 maintain the characteristics of advanced cancer. The authors also show that depletion of Mad2 or BubR1 decreases sensitivity to paclitaxel, but not to cisplatin (DNA cross-linking agent) or bleomycin (radiomimetic drug). Interestingly, the change in paclitaxel sensitivity of Mad2- or BubR1-depleted GC cells is not due to inhibition of apoptotic signaling but to the induction of senescence-like phenotypes, namely, senescence-associated β-galactosidase activation, p53 activation, and expression of the senescence-associated secretory phenotype factors IL-6 and IL-8. Importantly, in Mad2- or BubR1-depleted GC cells, senescence-like phenotypes are enhanced by paclitaxel treatment, suggesting that Mad2 and BubR1 suppress the induction of senescence. In short, SAC activity is critical to control apoptosis and senescence in paclitaxel-treated GC cells, although the details of the underlying molecular mechanisms remain elusive. These results have important implications and pave the way for future research of senescence-inducing chemotherapy in GC. Previous studies suggest that chemotherapeutic responses mediated by senescence have the potential to be a novel anti-cancer strategy.⁷ Further investigation of the contribution of Mad2 and BubR1 to cellular senescence and the underlying molecular mechanisms are required to understand the role of the SAC in paclitaxel-induced senescence and to open up the possibility of SAC components being used as a drug target for senescence-inducing chemotherapy.