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Research Paper|Volume 16, Issue 3|pp 2789—2811

Targeting PERK-ATF4-P21 axis enhances the sensitivity of osteosarcoma HOS cells to Mppα-PDT

Shenxi Zhong1,2, Ye Zhang1,2, Hai Mou1,2, Changchun Jian1,2, Qiu Huang1,2, Yunsheng Ou1,2
  • 1Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing 400016, China
  • 2Orthopedic Laboratory of Chongqing Medical University, Yuzhong, Chongqing 400016, China
* Equal contribution and co-first authors
Received: October 10, 2023Accepted: December 29, 2023Published: February 5, 2024
https://doi.org/10.18632/aging.205511

Copyright: © 2024 Zhong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Osteosarcoma (OS) is the most prevalent type of malignant bone tumor in adolescents. The overall survival of OS patients has reached a plateau recently. Thus, there is an urgent need to develop approaches to improve the sensitivity of OS to therapies. Pyropheophorbide-α methyl ester-mediated photodynamic therapy (MPPα-PDT) is a new type of tumor therapy, and elucidating its mechanism is helpful to improve its anti-tumor efficacy. Here, we investigated how PERK signaling promotes the human OS (HOS) cell survival induced by MPPα-PDT, as overcoming this may enhance sensitivity to MPPα-PDT. We found that MPPα-PDT combined with PERK inhibitor GSK2656157 enhanced HOS cell apoptosis by suppressing autophagy and p21. Autophagy inhibition and p21 depletion enhanced cell death, indicating pro-survival effects in MPPα-PDT. Notably, p21 was found to be an effector of the PERK-Atf4 pathway, which could positively regulate autophagy mediated by MPPα-PDT. In conclusion, we found that the combination of MPPα-PDT and GSK2656157 enhanced apoptosis in HOS cells by inhibiting autophagy. Mechanistically, this autophagy is p21-dependent and can be suppressed by GSK2656157, thereby enhancing sensitivity to MPPα-PDT.