Biochemical and biophysical research communications · 2026
p53-R248W evades doxorubicin mediated cell death through collective alteration in TOP2A and CYP1A1 genes in cancer cells.
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Mehrotra Megha, Shenoy Priti S, Sakpal Asmita, Chakraborty Sourav, Ray Pritha
Аннотация
BACKGROUND: Doxorubicin alone or in combination is widely used as first- or second-line chemotherapy in multiple solid tumors. Yet poor overall/progression-free survival and high mortality reflect the inherent Dox-resistance. Such resistance significantly limits the response to anthracycline-containing regimens. Frequent occurrence of TP53 mutations across cancers suggests that mutant-p53 may drive selective chemoresistance towards first- and second-line chemotherapeutics but the underlying mechanism remains inadequately explored.
METHODS: p53 hotspot mutations-R248W, R273H, R175H, R282W and wtp53 were overexpressed in p53-null ovarian (SKOV3) and gastric (KATOIII) cells. R248W mutant was also expressed in p53-null murine breast cancer (4T1) cells. MTT assay, immunoblotting and qPCR were used to assess drug sensitivity, apoptosis, autophagy and gene expression. Flow cytometry and immunofluorescence was used to assess cellular and nuclear doxorubicin levels.
RESULTS: p53-mutant expressing cells showed varied responses to cisplatin and doxorubicin. p53-R248W cells were sensitive to cisplatin but highly resistant to doxorubicin as measured by MTT assay and absence of PARP cleavage in multiple cancer cells. All mutants and wtp53 displayed differential degree of doxorubicin efflux. Doxorubicin-resistant p53-R248W SKOV3 cells could retain the drug, possibly due to decreased ABC transporter levels. Reduced BAX and TOP2A and hyperactivated CYP1A1/A2 levels were observed with doxorubicin-treatment in p53-R248W expressing ovarian, gastric and breast cancer cells.
CONCLUSION: p53-R248W confers selective doxorubicin resistance to multiple cancer cells through TOP2A suppression and CYP1A1/A2 overexpression. These findings highlight the mutation specific mechanism of doxorubicin resistance that might result in poor response and needs to be considered during treatment plan.
METHODS: p53 hotspot mutations-R248W, R273H, R175H, R282W and wtp53 were overexpressed in p53-null ovarian (SKOV3) and gastric (KATOIII) cells. R248W mutant was also expressed in p53-null murine breast cancer (4T1) cells. MTT assay, immunoblotting and qPCR were used to assess drug sensitivity, apoptosis, autophagy and gene expression. Flow cytometry and immunofluorescence was used to assess cellular and nuclear doxorubicin levels.
RESULTS: p53-mutant expressing cells showed varied responses to cisplatin and doxorubicin. p53-R248W cells were sensitive to cisplatin but highly resistant to doxorubicin as measured by MTT assay and absence of PARP cleavage in multiple cancer cells. All mutants and wtp53 displayed differential degree of doxorubicin efflux. Doxorubicin-resistant p53-R248W SKOV3 cells could retain the drug, possibly due to decreased ABC transporter levels. Reduced BAX and TOP2A and hyperactivated CYP1A1/A2 levels were observed with doxorubicin-treatment in p53-R248W expressing ovarian, gastric and breast cancer cells.
CONCLUSION: p53-R248W confers selective doxorubicin resistance to multiple cancer cells through TOP2A suppression and CYP1A1/A2 overexpression. These findings highlight the mutation specific mechanism of doxorubicin resistance that might result in poor response and needs to be considered during treatment plan.