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PRIMA-1 Targets the Vulnerability of Multiple Myeloma of Deregulated Protein Homeostasis through the Perturbation of ER Stress via p73 Demethylation (Oncotarget, Aug 2016)

Teoh PJ1,2, Bi C1, Sintosebastian C3, Tay LS4, Fonseca R3, Chng WJ1,3,2

1Cancer Science Institute Singapore, National University of Singapore, Singapore.
2Department of Haematology-Oncology, National University Cancer Institute, Singapore.
3Department of Hematology-Oncology, Mayo Clinic, Scottsdale, Arizona, USA.
4Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Abstract:

Despite therapeutic advancement, multiple myeloma (MM) remains incurable with drug resistance being one of the main challenges in the clinic. Myeloma cells possess high protein secretory load, leading to increased intracellular endoplasmic reticulum (ER) stress. Hence, they are vulnerable to further perturbation to its proteinhomeostasis. In studying the therapeutic mechanism of PRIMA-1 (mutant-p53-reactivating-agent), we uncovered its novel p53-independent-mechanism that can be exploited for myeloma. Despite its inability in restoring the wild type-p53 protein conformation and transcriptional function in the mutant-p53-human-myeloma-cells, PRIMA-1 was efficacious against myeloma cells with differential p53 genotypes. Strikingly, cells without p53 expression demonstrated highest drug sensitivity. Genome-wide gene-expression analysis revealed the involvement of ER stress/UPR-pathway in inducing PRIMA-1-toxicity. UPR markers, HSP70, CHOP and GADD34, were significantly up-regulated, concomitantly with the induction of apoptosis. Furthermore, there was a global attenuation of protein synthesis, correlated with phospho-eIF2a up-regulation. Mechanistically, we identified that PRIMA-1 could cause the demethylation of TP73, through DNMT1 depletion, to subsequently enhance UPR. Of clinical significance, we observed that PRIMA-1 had additive therapeutic effects with another UPR-inducing-agent, bortezomib. Importantly, it can partially re-sensitize bortezomib-resistant cells to bortezomib. Given that MM is already stressed at the baseline in the ER, our results implicated that PRIMA-1 is a potential therapeutic option in MM by targeting its Achilles heel.

KEYWORDS:

ER stress; PRIMA-1; bortezomib; multiple myeloma; p73

PMID: 27533450