p53 overexpression increases chemosensitivity in multidrug-resistant osteosarcoma cell lines

Abstract

Purpose Multidrug resistance (MDR) is a major obstacle to the successful treatment of osteosarcoma with chemotherapy. Effectiveness of cancer therapy correlates with the ability to induce a p53-dependent apoptotic response. p53 is a tumor suppressor gene that is mutated in 22% of osteosarcomas. While impaired p53 has been implicated in the oncogenesis of osteosarcoma, it is unclear whether overexpression of wild type p53 can increase chemosensitivity in MDR osteosarcoma cells. Methods We transfected a plasmid encoding the wild type p53 gene to MDR osteosarcoma cell lines, which have different p53 statuses, U-2OSR2 with wild type p53 (Wt-p53) and KHOSR2 with mutant p53 (Mt-p53), and determined the effect of p53 overexpression on chemosensitivities. Results Both of the U-2OSR2 and KHOSR2 cell lines displayed similar trends in p53 induced drug sensitivities. However, it seems that the impact of p53 overexpression is different based on the differential intrinsic p53 status in these cell lines. In the KHOSR2 cell line (Mt-p53), overexpression of p53 up-regulates the expression of pro-apoptotic protein p21 and Bax, while in the U-2OSR2 cell line (Wt-p53), overexpression of p53 down-regulates IGF-1r expression significantly. Conclusions These results demonstrated that tansfection of wild type p53 increases chemosensitivity through inhibiting either IGF-1r or through increasing the expression of pro-apoptotic proteins p21 and Bax in human MDR osteosarcoma cell lines.

Synergistic effects of cisplatin-caffeic acid induces apoptosis in human cervical cancer cells via the mitochondrial pathways

“…CDDP and CFC in combination may induce apoptosis by activating DNA damage. The present study is in agreement with that of Ye et al (40), which found that expression of p53 could lead to the induction of apoptosis by activating DNA damage in osteosarcoma cell lines. One limitation of the present study is that the expression of proteins involved in apoptotic pathways was not determined.…”

Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma

“…These results indicate that knock‐out mutant TP53 and restoration of the wild‐type TP53 function can increase the chemosensitivity of MDR osteosarcomas. Previously, we have reported that the overexpression of wild‐type TP53, through plasmid transfection, could enhance the effect of doxorubicin in the KHOSR2 cell line . Also, Zhang et al previously reported that mutant TP53 inhibits the activation of p73, leading to chemoresistance in tumors.…”

“…Previously, we have reported that the overexpression of wild-type TP53, through plasmid transfection, could enhance the effect of doxorubicin in the KHOSR2 cell line. 48 Also, Zhang et al previously reported that mutant TP53 inhibits the activation of p73, leading to chemoresistance in tumors. NSC59984 was able to restore the activity of p73, and consequently repaired the wild-type TP53 signaling pathway.…”

HOXA13 contributes to gastric carcinogenesis through DHRS2 interacting with MDM2 and confers 5‐FU resistance by a p53‐dependent pathway

“…In addition, mutant p53 (mutp53) is highly expressed in 40‐50% of all human tumors. Mutp53 generates aberrant proteins with abrogated tumor suppressor functions that can also acquire oncogenic gain‐of‐functions (GOF) that promotes malignant progression, invasion, metastasis and chemoresistance . SGC‐7901 was a cell line with mutated p53 (http://p53.free.fr).…”