Differential UVC radiation sensitivity in multidrug-resistant l1210 cells: Insights into p53 and Bcl-XL expression/function

Multidrug-resistant (MDR) variants of L1210 cells, selected for resistance to vincristine (R) or doxorubicin (D), exhibit elevated ABCB1 (P-glycoprotein) expression but differ in UVC sensitivity. D cells resemble parental L1210 (S) cells, whereas R cells are significantly more UVC vulnerable. To investigate this, we analyzed the expression of genes involved in DNA damage response, Trp53 family members, cyclin-dependent kinase inhibitors (p15, p21), Bcl-2 Family genes, and DNA repair genes in S, R, and D cells before and after UVC irradiation. The most striking difference was the absence of Trp53 expression in R cells at both mRNA and protein levels, while S and D cells expressed this gene. Instead, R cells uniquely expressed Trp63. CRISPR/Cas9-generated p53-null mutants of S and D cells showed increased UVC-induced cell death, but their sensitivity did not reach that of R cells. Bcl-xL, a protein linked to resistance against UVC-induced Apoptosis, was also reduced at both transcript and protein levels in R cells. Pharmacological inhibition of Bcl-xL in S and D cells with A-1155463 and A-1331852 enhanced UVC-induced cell death but did not replicate the high sensitivity observed in R cells. Our findings suggest that the heightened UVC sensitivity of R cells results from a combined deficiency of p53 and Bcl-xL, impairing DNA damage response and Apoptosis. These results reveal distinct molecular adaptations in MDR variants and provide insight into the mechanisms underlying differential UVC sensitivity.

ALL; Bcl-XL; Cell death; Multidrug resistance; P-glycoprotein; UVC irradiation; p53.