期刊
INTERNATIONAL JOURNAL OF MEDICAL SCIENCES
卷 18, 期 14, 页码 3197-3205出版社
IVYSPRING INT PUBL
DOI: 10.7150/ijms.61944
关键词
PTC; PTX; p53; cell cycle arrest; apoptosis
资金
- Foundation of National Natural Science Foundation of China [81702977]
- Sichuan Science and Technology Program [2021YFS0230, 2021YFS0228]
- Sichuan University West China Hospital Postdoctoral Science Foundation [2018HXBH016]
- Foundation of Sichuan University [2018SCUH0067]
- 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University [ZY2017309]
rAd-p53 sensitizes PTC cells to PTX by increasing p53 levels, leading to S arrest, G2/M arrest, and apoptosis. The combination of rAd-p53 + PTX inhibits tumor growth and induces apoptosis through p53-dependent mechanisms.
A functional p53 protein plays an important role in killing tumor cells. Previous studies showed that chemotherapeutic drug, paclitaxel (PTX), showed anti-tumor activity through inducing G2/M arrest and apoptosis by targeting microtubules in tumor cells. However, PTX was not sensitive to p53-inactivated papillary thyroid carcinoma (PTC) cells by inducing G2/M arrest only. Recombinant adenovirus-p53 (rAd-p53) was used to increase the level of p53, which significantly increased the sensitivity of PTC cells to PTX by inducing S arrest, G2/M arrest and apoptosis. To discuss the anti-tumor mechanism of rAd-p53 + PTX and found p53 activation was necessary for anti-tumor effect of PTX in PTC cells. There was high level of p53 in rAd-p53-treated PTC cells. rAd-p53 + PTX increased the level of p21, p-ATM and gamma-H2AX and decreased the level of Cyclin D1/E1, suggesting p53 activated p21 which negatively regulated cyclins to induce S arrest response to DNA damage in PTC cells. rAd-p53 + PTX increased the levels of cleaved-PARP-1, cleaved-Caspase 3, and BAX and decreased the level of BCL-XL, suggesting p53 regulates the expression of BAX/BCL-XL to mediate DNA damage-induced apoptosis in PTC cells. Furthermore, rAd-p53 + PTX showed significant tumor inhibition in TPC-1 xenograft model, with an inhibitory rate of 79.39%. TUNEL assay showed rAd-p53 + PTX induced notable apoptosis in tumor tissues. rAd-p53 showed good sensitization of PTX in vitro and in vivo through inducing DNA damage induced-apoptosis indicated p53-dependent apoptosis was essential for the antitumor effect of PTX in PTC.
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