Mitomycin–DNA Adducts Induce p53-Dependent and p53-Independent Cell Death Pathways

Boamah, Ernest K.; White, David E.; Talbott, Kathryn E.; Arva, Nicoleta C.; Berman, Daniel; Tomasz, Maria; Bargonetti, Jill

doi:10.1021/cb700060t

Cited by 36 publications

(46 citation statements)

References 33 publications

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“…We previously showed that DMC induces p53-independent cell death and DNA damage in human cancer cells [22], [23]. Very few pharmacological agents effectively enter into C. elegans, because of the thick cuticle of the animal, coupled with the animal’s extensive xenobiotic efflux pumps [33].…”

Section: Discussionmentioning

confidence: 99%

C. elegans CEP-1/p53 and BEC-1 Are Involved in DNA Repair

et al. 2014

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p53 is a transcription factor that regulates the response to cellular stress. Mammalian p53 functions as a tumor suppressor. The C. elegans p53, cep-1, regulates DNA-damage induced germline cell death by activating the transcription of egl-1 and ced-13. We used the C. elegans model to investigate how, in the whole animal, different forms of DNA damage can induce p53-dependent versus p53-independent cell death and DNA repair. DNA damage was induced by ultraviolet type C (UVC) radiation, or 10-decarbamoyl mitomycin C (DMC, an agent known to induce mammalian p53-independent cell death). Wild-type or cep-1 loss-of-function mutant animals were assayed for germline cell death and DNA lesions. Wild-type animals displayed greater removal of UVC-lesions over time, whereas cep-1 mutant animals displayed increased UVC-lesion retention. The cep-1 mutation increased UVC-lesion retention directly correlated with a reduction of progeny viability. Consistent with DMC inducing p53-independent cell death in mammalian cells DMC induced a C. elegans p53-independent germline cell death pathway. To examine the influence of wild-type CEP-1 and DNA damage on C. elegans tumors we used glp-1(ar202gf)/Notch germline tumor mutants. UVC treatment of glp-1 mutant animals activated the CEP-1 target gene egl-1 and reduced tumor size. In cep-1(gk138);glp-1(ar202gf) animals, UVC treatment resulted in increased susceptibility to lesions and larger tumorous germlines. Interestingly, the partial knockdown of bec-1 in adults resulted in a CEP-1-dependent increase in germline cell death and an increase in DNA damage. These results strongly support cross-talk between BEC-1 and CEP-1 to protect the C. elegans genome.

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Section: Discussionmentioning

confidence: 99%

C. elegans CEP-1/p53 and BEC-1 Are Involved in DNA Repair

et al. 2014

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“…Toxic effects of the drugs were determined by measuring the mitochondrial activity of each cell line using the tetrazolium dye-based micro-titration assay to measure mitochondrial dehydrogenases activity (20). Cells were seeded at 1.25 × 10 5 cells per well in 12 well plates and allowed to attach overnight.…”

Section: Methodsmentioning

confidence: 99%

8-Amino-Adenosine Activates p53-Independent Cell Death of Metastatic Breast Cancers

Polotskaia

Hoffman

Krett

et al. 2012

Molecular Cancer Therapeutics

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8-amino-adenosine (8-NH2-Ado) is a ribose sugar nucleoside analogue that reduces cellular ATP levels and inhibits mRNA synthesis. Estrogen receptor negative (ER−), metastatic breast cancers often contain mutant p53; therefore we asked if 8-NH2-Ado could kill breast cancer cells without activating the p53-pathway. Regardless of the breast cancer sub-type tested, or the p53 status of the cells, 8-NH2-Ado was more cytotoxic than either gemcitabine or etoposide. 8-NH2-Ado treatment inhibited cell proliferation, activated cell death, and did not activate transcription of the p53 target gene p21 or increase protein levels of either p53 or p21. This occurred in the estrogen receptor positive (ER+) MCF-7 cells that express wild-type p53, the ER+ T47-D cells that express mutant p53, and the ER-MDA-MB-468 cells or MDA-MB-231 cells that both express mutant p53. 8-NH2-Ado induced apoptotic death of MCF-7 cells and apoptosis was not inhibited by knockdown of functional p53. Moreover the pan-caspase inhibitor Z-VAD blocked the 8-NH2-Ado induced MCF-7 cell death. Interestingly 8-NH2-Ado caused the MDA-MB-231 cells to detach from the plate with only limited evidence of apoptotic cell death markers and the cell death was not inhibited by Z-VAD. Inhibition of MDA-MB-231 cell autophagy, by reduction of ATG7 or 3MA treatment, did not block this 8-NH2-Ado mediated cytotoxicity. Importantly 8-NH2-Ado was highly cytotoxic to triple negative breast cancer cells and worked through a pathway that did not require wild-type p53 for cytoxicity. Therefore, 8-NH2-Ado should be considered for the treatment of triple negative breast cancers that are chemotherapy resistant.

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“…The stalled replication fork then triggers several signalling pathways downstream that are involved in cell cycle arrest, repair or apoptosis 16 17. The current study shows that treatment with MMC also affects other cellular functions such as contraction and migration of the HNMFs when applied at sublethal concentrations.…”

Section: Discussionmentioning

confidence: 62%