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<p>Cervical cancer (CC) ranks as the third most common malignancy among women worldwide. Radiotherapy (RT) resistance represents a major cause of clinical treatment failure and disease progression. High-mobility group box-1 (HMGB1), a nuclear protein released during RT, has been implicated in the regulation of radiation resistance. This study aimed to establish HeLa RT-resistant (HeLa-R) cells and investigate the effect of HMGB1 on RT resistance and its underlying molecular pathway. HeLa-R cells were established through fractionated X-ray irradiation. Cell viability, proliferation, migration, and invasion were assessed using methyl thiazolyl tetrazolium (MTT), colony formation, Transwell migration, and invasion assays, respectively. HMGB1 expression was analyzed by quantitative RT-PCR, Western blot, and immunofluorescence. A phospho-kinase array was performed to evaluate phosphorylation levels of key kinase sites. Following fractionated X-ray irradiation, we successfully established HeLa-R cells, which exhibited significantly elevated HMGB1 expression compared to parental cells. HMGB1 knockdown suppressed RT resistance in HeLa-R cells, accompanied by increased phosphorylation of AMP-activated protein kinase (p-AMPK). Conversely, AMPK inhibition restored cell viability, colony formation, migration, and invasion in HMGB1-deficient HeLa-R cells. Mechanistically, in HeLa-R cells, mTOR was identified as a downstream effector of AMPK signaling. Separately, clinical analysis revealed that HMGB1 levels were significantly elevated, while p-AMPK levels were markedly reduced in tumor tissues from radioresistant patients compared with radiosensitive patients. In conclusion, our in vitro findings demonstrate that HMGB1 inhibition suppresses RT resistance in HeLa-R cells through activation of the AMPK/mTOR pathway. The clinical correlations between HMGB1, p-AMPK, and radiotherapy response support the potential relevance of this pathway, although further validation in patient tissues is required.</p>

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HMGB1 promotes radiotherapy resistance in human cervical cancer HeLa cells through regulating the AMPK/mTOR signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • Youyou Xie,
  • Changhui Yu,
  • Miao Wang,
  • Yaqin Lin,
  • Biyun Wang

摘要

Cervical cancer (CC) ranks as the third most common malignancy among women worldwide. Radiotherapy (RT) resistance represents a major cause of clinical treatment failure and disease progression. High-mobility group box-1 (HMGB1), a nuclear protein released during RT, has been implicated in the regulation of radiation resistance. This study aimed to establish HeLa RT-resistant (HeLa-R) cells and investigate the effect of HMGB1 on RT resistance and its underlying molecular pathway. HeLa-R cells were established through fractionated X-ray irradiation. Cell viability, proliferation, migration, and invasion were assessed using methyl thiazolyl tetrazolium (MTT), colony formation, Transwell migration, and invasion assays, respectively. HMGB1 expression was analyzed by quantitative RT-PCR, Western blot, and immunofluorescence. A phospho-kinase array was performed to evaluate phosphorylation levels of key kinase sites. Following fractionated X-ray irradiation, we successfully established HeLa-R cells, which exhibited significantly elevated HMGB1 expression compared to parental cells. HMGB1 knockdown suppressed RT resistance in HeLa-R cells, accompanied by increased phosphorylation of AMP-activated protein kinase (p-AMPK). Conversely, AMPK inhibition restored cell viability, colony formation, migration, and invasion in HMGB1-deficient HeLa-R cells. Mechanistically, in HeLa-R cells, mTOR was identified as a downstream effector of AMPK signaling. Separately, clinical analysis revealed that HMGB1 levels were significantly elevated, while p-AMPK levels were markedly reduced in tumor tissues from radioresistant patients compared with radiosensitive patients. In conclusion, our in vitro findings demonstrate that HMGB1 inhibition suppresses RT resistance in HeLa-R cells through activation of the AMPK/mTOR pathway. The clinical correlations between HMGB1, p-AMPK, and radiotherapy response support the potential relevance of this pathway, although further validation in patient tissues is required.