Talks
Presentation Type
Oral Presentation
Discipline Track
Biomedical Science
Abstract Type
Research/Clinical
Abstract
Background: Mortalin, a member of the Hsp70 family of proteins, enriched in many types of cancers, has been shown to promote carcinogenesis and metastasis by multiple ways of which inactivation of p53 has been firmly established. Downregulation of mortalin by small RNAs and disruption of mortalin-p53 interactions by small molecules have earlier been shown to activate tumor suppressor activities of p53 yielding growth arrest/apoptosis in cancer cells. In this premise, screening of a chemical library to identify potential abrogators of mortalin-p53 interaction was performed using two-way imaging assay involving (i) shift of mortalin staining pattern from perinuclear (characteristics of cancer cells) to pancytoplasmic (characteristics of normal cells) and (ii) nuclear enrichment of p53. Using these assays in four rounds of screenings of a chemical library, three compounds Mortaparib, MortaparibPlus and Mortalparibmild were identified [1-4]. They showed similar structure and caused inactivation of mortalin and PARP1 activities.
Methods: In the current study, we investigated response of cancer cells, varying in their p53 status (wild, mutant or null), to mortaparibs. Molecular signalings involved in cell proliferation, growth arrest, apoptosis, was determined by biochemical, imaging and expression analyses in control and Mortaparib (Mortaparibmild (4-[(4-amino-5-thiophen-2-yl-1,2,4-triazol-3-yl)sulfanylmethyl]-N-(4-methoxyphenyl)-1,3-thiazol-2-amine, in particular) treated cells.
Results: We report that MortaparibMild, although with relatively weaker efficacy as compared to MortaparibandMortaparibplus, cause growth arrest or apoptosis in cancer cells by downregulation of mortalin and PARP-1 activities in p53-dependent and -independent pathways. Low nontoxic concentrations of the three Mortaparibs caused inhibition of cell migration, invasion and clusterization that was supported by molecular markers involved in these characteristics of cancer cells. Of note, in these assays, MortaparibMild showed good efficacy. These data suggested the three Mortaparibs possess differential activities that may be recruited for treatment of different stages of cancer targeting proliferation, metastasis and relapse of cancer.
Conclusions: Taken together, we report anti-cancer activity of three mortaparibs (MortaparibMild in particular)and their differential use in cancer management that warrants further attention in laboratory and clinical studies.
Academic/Professional Position
Graduate Student
Recommended Citation
Yang, Shi; Zhang, Huayue; Kim, Hyonchol; Kaul, Sunil; and Wadhwa, Renu, "Molecular insights into the anti-stress function of fucoxanthin, a major component of an edible seaweed (wakame)" (2024). Research Symposium. 6.
https://scholarworks.utrgv.edu/somrs/2023/talks/6
Included in
Molecular insights into the anti-stress function of fucoxanthin, a major component of an edible seaweed (wakame)
Background: Mortalin, a member of the Hsp70 family of proteins, enriched in many types of cancers, has been shown to promote carcinogenesis and metastasis by multiple ways of which inactivation of p53 has been firmly established. Downregulation of mortalin by small RNAs and disruption of mortalin-p53 interactions by small molecules have earlier been shown to activate tumor suppressor activities of p53 yielding growth arrest/apoptosis in cancer cells. In this premise, screening of a chemical library to identify potential abrogators of mortalin-p53 interaction was performed using two-way imaging assay involving (i) shift of mortalin staining pattern from perinuclear (characteristics of cancer cells) to pancytoplasmic (characteristics of normal cells) and (ii) nuclear enrichment of p53. Using these assays in four rounds of screenings of a chemical library, three compounds Mortaparib, MortaparibPlus and Mortalparibmild were identified [1-4]. They showed similar structure and caused inactivation of mortalin and PARP1 activities.
Methods: In the current study, we investigated response of cancer cells, varying in their p53 status (wild, mutant or null), to mortaparibs. Molecular signalings involved in cell proliferation, growth arrest, apoptosis, was determined by biochemical, imaging and expression analyses in control and Mortaparib (Mortaparibmild (4-[(4-amino-5-thiophen-2-yl-1,2,4-triazol-3-yl)sulfanylmethyl]-N-(4-methoxyphenyl)-1,3-thiazol-2-amine, in particular) treated cells.
Results: We report that MortaparibMild, although with relatively weaker efficacy as compared to MortaparibandMortaparibplus, cause growth arrest or apoptosis in cancer cells by downregulation of mortalin and PARP-1 activities in p53-dependent and -independent pathways. Low nontoxic concentrations of the three Mortaparibs caused inhibition of cell migration, invasion and clusterization that was supported by molecular markers involved in these characteristics of cancer cells. Of note, in these assays, MortaparibMild showed good efficacy. These data suggested the three Mortaparibs possess differential activities that may be recruited for treatment of different stages of cancer targeting proliferation, metastasis and relapse of cancer.
Conclusions: Taken together, we report anti-cancer activity of three mortaparibs (MortaparibMild in particular)and their differential use in cancer management that warrants further attention in laboratory and clinical studies.