Ultrasound-triggered microbubble destruction enhances the radiosensitivity of glioblastoma by inhibiting PGRMC1-mediated autophagy <italic style="font-style: italic">in vitro</italic> and <italic style="font-style: italic">in vivo</italic>

Ying He; Xun-Hu Dong; Qiong Zhu; Ya-Li Xu; Ming-Liang Chen; Zheng Liu

doi:10.1186/s40779-022-00369-0

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Ultrasound-triggered microbubble destruction enhances the radiosensitivity of glioblastoma by inhibiting PGRMC1-mediated autophagy in vitro and in vivo

RESEARCH | Updated：2023-02-28

- Ultrasound-triggered microbubble destruction enhances the radiosensitivity of glioblastoma by inhibiting PGRMC1-mediated autophagy in vitro and in vivo
- Military Medical Research Vol. 9, Issue 3, Pages: 331-350(2022)
- Affiliations：
  
  1.Department of Ultrasound, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
  2.Department of Chemical Defense Medicine, School of Military Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing 400038, China
  3.Institute of Toxicology, School of Military Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing 400038, China
  4.Institute of Pathology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
- Author bio：
  
  * chenmingliang1987@163.com;
  liuzhengs@163.com
- Funds：
- DOI：10.1186/s40779-022-00369-0
  CLC：
- Published：2022-06
- Accepted：
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He et al.: Ultrasound-triggered microbubble destruction enhances the radiosensitivity of glioblastoma by inhibiting PGRMC1-mediated autophagy in vitro and in vivo. Mil Med Res, 2022, 9: 9.
DOI：

He et al.: Ultrasound-triggered microbubble destruction enhances the radiosensitivity of glioblastoma by inhibiting PGRMC1-mediated autophagy in vitro and in vivo. Mil Med Res, 2022, 9: 9. DOI： 10.1186/s40779-022-00369-0.

摘要

Abstract

Background:

Ultrasound-triggered microbubble destruction (UTMD) is a widely used noninvasive technology in both military and civilian medicine

which could enhance radiosensitivity of various tumors. However

little information is available regarding the effects of UTMD on radiotherapy for glioblastoma or the underlying mechanism. This study aimed to delineate the effect of UTMD on the radiosensitivity of glioblastoma and the potential involvement of autophagy.

Methods:

GL261

U251 cells and orthotopic glioblastoma-bearing mice were treated with ionizing radiation (IR) or IR plus UTMD. Autophagy was observed by confocal microscopy and transmission electron microscopy. Western blotting and immunofluorescence analysis were used to detect progesterone receptor membrane component 1 (PGRMC1)

light chain 3 beta 2 (LC3B2) and sequestosome 1 (SQSTM1/p62) levels. Lentiviral vectors or siRNAs transfection

and fluorescent probes staining were used to explore the underlying mechanism.

Results:

UTMD enhanced the radiosensitivity of glioblastoma

in vitro

and

in vivo

(

0.01). UTMD inhibited autophagic flux by disrupting autophagosome-lysosome fusion without impairing lysosomal function or autophagosome synthesis in IR-treated glioblastoma cells. Suppression of autophagy by 3-methyladenine

bafilomycin A1 or ATG5 siRNA had no significant effect on UTMD-induced radiosensitization in glioblastoma cells (

0.05). Similar results were found when autophagy was induced by rapamycin or ATG5 overexpression (P

0.05). Furthermore

UTMD inhibited PGRMC1 expression and binding with LC3B2 in IR-exposed glioblastoma cells (

0.01). PGRMC1 inhibitor AG-205 or PGRMC1 siRNA pretreatment enhanced UTMD-induced LC3B2 and p62 accumulation in IR-exposed glioblastoma cells

thereby promoting UTMD-mediated radiosensitization (

0.05). Moreover

PGRMC1 overexpression abolished UTMD-caused blockade of autophagic degradation

subsequently inhibiting UTMD-induced radiosensitization of glioblastoma cells. Finally

compared with IR plus UTMD group

PGRMC1 overexpression significantly increased tumor size [(3.8±1.1) mm

. (8.0±1.9) mm

0.05] and decreased survival time [(67.2±2.6) d

. (40.0±1.2) d

=0.0026] in glioblastoma-bearing mice.

Conclusions:

UTMD enhanced the radiosensitivity of glioblastoma partially by disrupting PGRMC1-mediated autophagy.

关键词

Keywords

references

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⁰

Ultrasound-triggered microbubble destruction enhances the radiosensitivity of glioblastoma by inhibiting PGRMC1-mediated autophagy in vitro and in vivo

DOI：10.1186/s40779-022-00369-0

摘要

Abstract

关键词

Keywords

references