MEDB-08. Inhibition of different mitotic targets demonstrated distinct DNA damage and cell death response in p53-mutant medulloblastoma
Year: 2022
Type: conference-abstract
Abstract: BACKGROUND: In normal cells, cell cycle is tightly regulated by mitotic proteins to ensure smooth transition through each phase of cell division. Here, we examine two proteins – KIF11, a mitotic kinesin, responsible for assembly and maintenance of mitotic spindle during mitosis; and MELK, a serine/threonine kinase, essential for mitotic progression. Cancer cells can upregulate MELK and KIF11 to promote uncontrolled cell division and protect the cells from apoptotic cell death, leading to tumorigenesis. AIMS: We investigated the response of p53-mutant medulloblastoma (MB) by inhibiting KIF11 and MELK separately to study the effects on cell cycle progression and cell death mechanisms. RESULTS: Cell proliferation was suppressed by inhibition of either KIF11 or MELK in MB, independent of p53-mutant status. Regardless of p53-mutant status, inhibiting KIF11 induced cell cycle arrest at G2/M. In contrast, inhibiting MELK (IC50 dose) induced more prominent G2/M arrest in p53-mutant cells compared to p53-wildtype cells. In p53-mutant MB, arrested cells during MELK inhibition subsequently underwent apoptotic cell death at 24h and 48h. With KIF11 inhibition, p53-mutant cells at 24h were already in necrotic stage. p53-mutant cells reached necrotic stage in a shorter time with KIF11 inhibition than MELK inhibition. On immunoblotting, independent of p53-mutant status, KIF11 inhibition produces more significant increase in DNA damage marker and c-PARP indicative of apoptosis, compared to MELK inhibition. Treatment with KIF11 or MELK inhibitor increased p53 protein expression in p53-wildtype (normal stress response). However, in p53-mutant cells, p53 protein expression decreased post-KIF11-inhibition, but remained unchanged post-MELK inhibition. In-vivo, inhibiting KIF11 was less tolerable in a patient-derived orthotopic xenograft model with p53-mutation. CONCLUSION: Inhibition of either mitotic target KIF11 or MELK, can induce anti-proliferative effects in MB. In p53-mutant MB, DNA damage and cell death response with KIF11-inhibition are more marked.
Source: Neuro-Oncology
Institutions: SingHealth, SingHealth Duke-NUS Academic Medical Centre, Duke-NUS Medical School, National Cancer Centre Singapore, Northwestern University, University of Connecticut, Connecticut Children's Medical Center, The Jackson Laboratory for Genomic Medicine, Texas Children's Hospital, Agency for Science, Technology and Research, Institute of Molecular and Cell Biology
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,612
OpenAlex ID: W4281786221