Mitomycin C and decarbamoyl mitomycin C induce p53-independent p21WAF1/CIP1 activation.
Mitomycin C (MC), a commonly used anticancer drug, induces DNA damage via DNA alkylation. Decarbamoyl mitomycin C (DMC), another mitomycin lacking the carbamate at C10, generates similar lesions as MC. Interstrand cross-links (ICLs) are believed to be the lesions primarily responsible for the cytotoxicity of MC and DMC. The major ICL generated by MC (α-ICL) has a trans stereochemistry at the guanine-drug linkage whereas the major ICL from DMC (β-ICL) has the opposite, cis, stereochemistry. In addition, DMC can provoke strong p53-independent cell death. Our hypothesis is that the stereochemistry of the major unique β-ICL generated by DMC is responsible for this p53-independent cell death signaling. p53 gene is inactively mutated in more than half of human cancers. p21WAF1/CIP1 known as a major effector of p53 is involved in p53-dependent and -independent control of cell proliferation and death. This study revealed the role of p21WAF1/CIP1 on MC and DMC triggered cell damage. MCF-7 (p53-proficient) and K562 (p53-deficient) cells were used. Cell cycle distributions were shifted to the G1/S phase in MCF-7 treated with MC and DMC, but were shifted to the S phase in K562. p21WAF1/CIP1 activation was observed in both cells treated with MC and DMC, and DMC triggered more significant activation. Knocking down p53 in MCF-7 did not attenuate MC and DMC induced p21WAF1/CIP1 activation. The α-ICL itself was enough to cause p21WAF1/CIP1 activation.
Department of Sciences, John Jay College of Criminal Justice, City University of New York, NY 10019, USA.
Shu-Yuan
SY
Cheng
Department of Sciences, John Jay College of Criminal Justice, City University of New York, NY 10019, USA.
Jiwon
J
Seo
Department of Sciences, John Jay College of Criminal Justice, City University of New York, NY 10019, USA.
Bik Tzu
BT
Huang
Department of Sciences, John Jay College of Criminal Justice, City University of New York, NY 10019, USA.
Tanya
T
Napolitano
Department of Sciences, John Jay College of Criminal Justice, City University of New York, NY 10019, USA.
Elise
E
Champeil
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells; D061986:MCF-7 Cells; D016685:Mitomycin / Q000737:chemistry* / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016685:Mitomycin
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