title: PRIMA-1 targets the vulnerability of multiple myeloma of deregulated protein homeostasis through the perturbation of ER stress via p73 demethylation.
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 protein homeostasis. 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.
authors.affiliation: Cancer Science Institute Singapore, National University of Singapore, Singapore.|Department of Haematology-Oncology, National University Cancer Institute, Singapore.
authors.forename: Phaik Ju
authors.initials: PJ
authors.lastname: Teoh
authors.affiliation: Cancer Science Institute Singapore, National University of Singapore, Singapore.
authors.forename: Chonglei
authors.initials: C
authors.lastname: Bi
authors.affiliation: Department of Hematology-Oncology, Mayo Clinic, Scottsdale, Arizona, USA.
authors.forename: Chirackal
authors.initials: C
authors.lastname: Sintosebastian
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Liang Seah
authors.initials: LS
authors.lastname: Tay
authors.affiliation: Department of Hematology-Oncology, Mayo Clinic, Scottsdale, Arizona, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Fonseca
authors.affiliation: Cancer Science Institute Singapore, National University of Singapore, Singapore.|Department of Hematology-Oncology, Mayo Clinic, Scottsdale, Arizona, USA.|Department of Haematology-Oncology, National University Cancer Institute, Singapore.
authors.forename: Wee Joo
authors.initials: WJ
authors.lastname: Chng
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D017209:Apoptosis; D000069286:Bortezomib / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000378:metabolism*; D019175:DNA Methylation; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004722:Endoribonucleases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D055106:Genome-Wide Association Study; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D009101:Multiple Myeloma / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic; D000072160:Tumor Protein p73 / Q000378:metabolism*; D056811:Unfolded Protein Response; D015854:Up-Regulation
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C446290:PRIMA1 protein, human; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D000069286:Bortezomib; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619380:DNMT1 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases
keywords: ER stress; PRIMA-1; bortezomib; multiple myeloma; p73