The molecular and clinical verification of therapeutic resistance via the p38 MAPK-Hsp27 axis in lung cancer

Abstract

Treatment failure followed by relapse and metastasis in patients with non-small cell lung cancer is often the result of acquired resistance to cisplatin-based chemotherapy. A cancer stem cell (CSC)-mediated anti-apoptotic phenomenon is responsible for the development of drug resistance. The underlying molecular mechanism related to cisplatin resistance is still controversial, and a new strategy is needed to counteract cisplatin resistance. We used a nonadhesive culture system to generate drug-resistant spheres (DRSPs) derived from cisplatin-resistant H23 lung cancer cells. The expressions of drug-resistance genes, properties of CSCs, and markers of anti-apoptotic proteins were compared between control cells and DRSPs. DRSPs exhibited upregulation of cisplatin resistance-related genes. Gradual morphological alterations showing epithelial-to-mesenchymal transition phenomenon and increased invasion and migration abilities were seen during induction of DRSPs. Compared with control cells, DRSPs displayed increased CSC and anti-apoptotic properties, greater resistance to cisplatin, and overexpression of p-Hsp27 via activation of p38 MAPK signaling. Knockdown of Hsp27 or p38 decreased cisplatin resistance and increased apoptosis in DRSPs. Clinical studies confirmed that the expression of p-Hsp27 was closely associated with prognosis. Overexpression of p-Hsp27 was usually detected in advanced-stage patients with lung cancer and indicated short survival.SummaryDRSPs were useful for investigating drug resistance and may provide a practical model for studying the crucial role of p-Hsp27 in the p38 MAPK–Hsp27 axis in CSC-mediated cisplatin resistance. Targeting this axis using siRNA Hsp27 may provide a treatment strategy to improve prognosis and prolong survival in lung cancer patients.

IL-8 signaling is involved in resistance of lung carcinoma cells to erlotinib

“…These kinases remained highly upregulated in HCC827 resistant cells following 48-hour erlotinib withdrawal. Hsp27, a protein that facilitates refolding of damaged proteins in response to stress conditions, has been shown to mediate resistance to apoptosis, in particular in response to cytotoxic drugs [27]. Interestingly, Hsp27 is a downstream target of the p38 kinase [28], a result that further supports our observations regarding enhanced p38 kinase activity in the erlotinib-resistant cells.…”

The role of HSP27 in the development of drug resistance of gastrointestinal malignancies: Current status and perspectives

“…Moreover, the expression of HSPs is upregulated in response to stressful conditions, including exposure to oxidative stress, toxins, and high temperatures (Morrow et al, ). Consistently, previous studies have shown that a higher levels of HSP27 may be associated with a poor prognosis (Ciocca & Calderwood, ) and an increased resistance to chemotherapeutic drugs in several malignancies including larynx carcinoma (Mazurov et al, ), breast cancer (Oesterreich et al, ), and lung cancer (Liu et al, ), whereas decrease in HSP27 restores drug sensitivity in cancers. Additionally, further studies have shown that targeting HSP27 may be a novel approach of overcoming chemotherapy drug resistance in these malignancies (Taba et al, ; Tsuruta et al, ; Yang et al, ).…”

Inhibition of endoplasmic reticulum (ER) stress sensors sensitizes cancer stem-like cells to ER stress-mediated apoptosis

“…On the other hand, cisplatin-resistant cancer cells including CSC have the ability to evade cisplatin-induced apoptosis [26, 27]. Since our results indicated that the sphere-forming cells of cervical cancer evaded ER stress-mediated apoptosis, we addressed differences in UPR in response to cisplatin between monolayer and sphere-forming cells.…”