Palbociclib Induces the Apoptosis of Lung Squamous Cell Carcinoma Cells via RB-Independent STAT3 Phosphorylation

Abstract

Lung squamous cell carcinoma (LUSC) treatment response is poor and treatment alternatives are limited. Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, has recently been approved for hormone receptor-positive breast cancer patients and applied in multiple preclinical models, but its use for LUSC therapy remains elusive. Here, we investigated whether palbociclib induced cell apoptosis and dissected the underlying mechanism in LUSC. We found that palbociclib induced LUSC cell apoptosis through inhibition of Src tyrosine kinase/signal transducers and activators of transcription 3 (STAT3). Interestingly, palbociclib reduced STAT3 signaling in LUSC cells interfered by retinoblastoma tumor-suppressor gene (RB), suggesting that pro-apoptosis effect of palbociclib was independent of classic CDK4/6-RB signaling. Furthermore, palbociclib could suppress IL-1β and IL-6 expression, and therefore blocked Src/STAT3 signaling, which were rescued by either recombinant human IL-1β or IL-6. Moreover, Myc mediated the sensitivity of LUSC cells to palbociclib. Our discoveries demonstrated that palbociclib induces apoptosis of LUSC cells through the Src/STAT3 axis in an RB-independent manner, and provided a reliable experimental basis of clinical studies in LUSC patients.

Nanoparticle-Mediated Delivery of STAT3 Inhibitors in the Treatment of Lung Cancer

“…Recently, cyclin-dependent kinase (CDK) family members, which were supposed to regulate the cell cycle, were demonstrated to promote RNA synthesis in genetic processes by regulating the STAT3 signaling pathway [66]. Therefore, CDK inhibitors successfully reduced the expressions of pSTAT3 and transcriptional target genes such as cyclin B1 and IL-6, leading to apoptosis of lung squamous cell carcinoma (LUSC) cells and inhibition of tumor growth in patient-derived xenograft (PDX) models [66,67]. In addition, the DNA damage-induced apoptosis suppressor (DDIAS) has been reported to promote the progression of lung cancer through the regulation of the STAT3 pathway, and DDIAS inhibitors were found to suppress the activation of c-Jun NH(2)-terminal kinase (JNK) or interfere with DDIAS/STAT3 binding [68,69].…”