Research Spotlight

α-Fodrin–CENP-E interaction is critical for pancreatic cancer progression and drug response

Cell Cycle | 2025 Apr 10:1-25 | DOI: 10.1080/15384101.2025.2485837

Jyothy A, Hussain J, S SC, Chandraprabha VR, Nair MG, Vasudevan S, Sreedharan H, Abraham B, Maliekal TT, Natarajan K, Sengupta S

ABSTRACT

α-Fodrin, a known scaffolding protein for cytoskeleton stabilization, performs various functions including cell adhesion, cell motility, DNA repair and apoptosis. Based on our previous results revealing its role in mitosis in glioblastoma, we have examined its effect in pancreatic cancer, which is often linked to mitotic aberrations including aneuploidy and chromosome instability. Here, we show that the expression of α-Fodrin increases in pancreatic adenocarcinoma tissues compared to its normal counterpart, suggesting its tumor promoting role. shRNA-mediated knock-down of α-Fodrin significantly reduces the xenograft growth in immunocompromised mice underscoring the importance of α-Fodrin in tumor progression. CENP-E (centromere-associated protein E) is a motor protein essential for chromosomal alignment and segregation during mitosis. We have found that α-Fodrin interacts with CENP-E to recruit it to the kinetochore and depletion of α-Fodrin has a crucial role in controlling aneuploidy. As these mitotic defects can lead to apoptosis, we have further evaluated the activation of possible upstream pathways. Paclitaxel, a chemotherapeutic agent that stabilizes microtubules, disrupts mitosis and induces apoptosis. We found that Paclitaxel triggered stronger activation of JNK, ERK, and P38 MAPKs, altered BCL2/BAX ratios, cytochrome C release causing increased apoptosis in α-Fodrin knockdown cells compared to cells with wild-type α-Fodrin. This enhanced sensitivity to paclitaxel is consistent with improved survival in pancreatic cancer patients with low α-Fodrin (SPTAN1) and low CENP-E expression compared to poor prognosis with high expressions of both the genes. Taken together, this study provides the molecular mechanism by which α-Fodrin - CENP-E axis regulates pancreatic cancer progression and drug response.