FAM193A is a positive regulator of p53 activity

Szwarc, Maria M.; Guarnieri, Anna L.; Joshi, Molishree; Duc, Huy Nguyen; Laird, Madison C.; Pandey, Ahwan; Khanal, Santosh; Dohm, Emily; Bui, Aimee K.; Sullivan, Kelly D.; Galbraith, Matthew D.; Andrysík, Zdeněk; Espinosa, Joaquín M.

doi:10.1016/j.celrep.2023.112230

Cited by 2 publications

(2 citation statements)

References 101 publications

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“…Ferroptosis has been suggested to require WTp53 activity [ 41 ]. In addition, recent reports suggest the degree of FAM193A expression is a widespread enabler of p53 activity in cell death [ 46 ], which may relate to the differential ferroptosis sensitivity of HT-29 and HCT 116.…”

Section: Discussionmentioning

confidence: 99%

Ferroptosis-Mediated Cell Death Induced by NCX4040, The Non-Steroidal Nitric Oxide Donor, in Human Colorectal Cancer Cells: Implications in Therapy

Sinha

Bortner

Jarmusch

et al. 2023

Cells

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Our recent studies show that the treatment of human ovarian tumor cells with NCX4040 results in significant depletions of cellular glutathione, the formation of reactive oxygen/nitrogen species and cell death. NCX4040 is also cytotoxic to several human colorectal cancer (CRC) cells in vitro and in vivo. Here, we examined the ferroptosis-dependent mechanism(s) of cytotoxicity of NCX4040 in HT-29 and K-RAS mutant HCT 116 colon cell lines. Ferroptosis is characterized by the accumulation of reactive oxygen species (ROS) within the cell, leading to an iron-dependent oxidative stress-mediated cell death. However, its relevance in the mechanism of NCX4040 cytotoxicity in CRCs is not known. We found that NCX4040 generates ROS in CRC cells without any depletion of cellular GSH. Combinations of NCX4040 with erastin (ER) or RSL3 (RAS-selective lethal 3), known inducers of ferroptosis, enhanced CRC death. In contrast, ferrostatin-1, an inhibitor of ferroptosis, significantly inhibited NCX4040-induced cell death. Treatment of CRC cells with NCX4040 resulted in the induction of lipid peroxidation in a dose- and time-dependent manner. NCX4040 treatment induced several genes related to ferroptosis (e.g., CHAC1, GPX4 and NOX4) in both cell lines. Metabolomic studies also indicated significant increases in both lipid and energy metabolism following the drug treatment in HT-29 and HCT 116 cells. These observations strongly suggest that NCX4040 causes the ferroptosis-mediated cell death of CRC cells. Furthermore, combinations of NCX4040 and ER or RSL3 may contribute significantly to the treatment of CRC, including those that are difficult to treat due to the presence of Ras mutations in the clinic. NCX4040-induced ferroptosis may also be a dynamic form of cell death for the treatment of other cancers.

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Section: Discussionmentioning

confidence: 99%

Ferroptosis-Mediated Cell Death Induced by NCX4040, The Non-Steroidal Nitric Oxide Donor, in Human Colorectal Cancer Cells: Implications in Therapy

Sinha

Bortner

Jarmusch

et al. 2023

Cells

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“…These results indicate that MDM4, in addition to inhibiting transcriptional activity of p53, contributes to the degradation of p53 by facilitating the E3 ligase activity of MDM2. FAM193A interacts with and destabilizes MDM4, thereby enhancing p53 transcriptional activity [111].…”

Section: The P53 Pathwaymentioning

confidence: 99%

Expanding Roles of the E2F-RB-p53 Pathway in Tumor Suppression

Zhou,

Nakajima,

Shirasawa

et al. 2023

Biology

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The transcription factor E2F links the RB pathway to the p53 pathway upon loss of function of pRB, thereby playing a pivotal role in the suppression of tumorigenesis. E2F fulfills a major role in cell proliferation by controlling a variety of growth-associated genes. The activity of E2F is controlled by the tumor suppressor pRB, which binds to E2F and actively suppresses target gene expression, thereby restraining cell proliferation. Signaling pathways originating from growth stimulative and growth suppressive signals converge on pRB (the RB pathway) to regulate E2F activity. In most cancers, the function of pRB is compromised by oncogenic mutations, and E2F activity is enhanced, thereby facilitating cell proliferation to promote tumorigenesis. Upon such events, E2F activates the Arf tumor suppressor gene, leading to activation of the tumor suppressor p53 to protect cells from tumorigenesis. ARF inactivates MDM2, which facilitates degradation of p53 through proteasome by ubiquitination (the p53 pathway). P53 suppresses tumorigenesis by inducing cellular senescence or apoptosis. Hence, in almost all cancers, the p53 pathway is also disabled. Here we will introduce the canonical functions of the RB-E2F-p53 pathway first and then the non-classical functions of each component, which may be relevant to cancer biology.

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FAM193A is a positive regulator of p53 activity

Cited by 2 publications

References 101 publications

Ferroptosis-Mediated Cell Death Induced by NCX4040, The Non-Steroidal Nitric Oxide Donor, in Human Colorectal Cancer Cells: Implications in Therapy

Ferroptosis-Mediated Cell Death Induced by NCX4040, The Non-Steroidal Nitric Oxide Donor, in Human Colorectal Cancer Cells: Implications in Therapy

Expanding Roles of the E2F-RB-p53 Pathway in Tumor Suppression

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