Dataset Information

GADD45? sensitizes cervical cancer cells to radiotherapy via increasing cytoplasmic APE1 level.

ABSTRACT: Radioresistance remains a major clinical challenge in cervical cancer therapy. However, the mechanism for the development of radioresistance in cervical cancer is unclear. Herein, we determined that growth arrest and DNA-damage-inducible protein 45? (GADD45?) is decreased in radioresistant cervical cancer compared to radiosensitive cancer both in vitro and in vivo. In addition, silencing GADD45? prevents cervical cancer cells from undergoing radiation-induced DNA damage, cell cycle arrest, and apoptosis. More importantly, our data show that the overexpression of GADD45? significantly enhances the radiosensitivity of radioresistant cervical cancer cells. These data show that GADD45? decreases the cytoplasmic distribution of APE1, thereby enhancing the radiosensitivity of cervical cancer cells. Furthermore, we show that GADD45? inhibits the production of nitric oxide (NO), a nuclear APE1 export stimulator, by suppressing both endothelial NO synthase (eNOS) and inducible NO synthase (iNOS) in cervical cancer cells. In conclusion, our findings suggest that decreased GADD45? expression significantly contributes to the development of radioresistance and that ectopic expression of GADD45? sensitizes cervical cancer cells to radiotherapy. GADD45? inhibits the NO-regulated cytoplasmic localization of APE1 through inhibiting eNOS and iNOS, thereby enhancing the radiosensitivity of cervical cancer cells.

SUBMITTER: Li Q

PROVIDER: S-EPMC5943293 | biostudies-other | 2018 May

REPOSITORIES: biostudies-other

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GADD45α sensitizes cervical cancer cells to radiotherapy via increasing cytoplasmic APE1 level.

Li Qing Q Wei Xi X Zhou Zhi-Wei ZW Wang Shu-Nan SN Jin Hua H Chen Kui-Jun KJ Luo Jia J Westover Kenneth D KD Wang Jian-Min JM Wang Dong D Xu Cheng-Xiong CX Shan Jin-Lu JL

Cell death & disease 20180501 5

Radioresistance remains a major clinical challenge in cervical cancer therapy. However, the mechanism for the development of radioresistance in cervical cancer is unclear. Herein, we determined that growth arrest and DNA-damage-inducible protein 45α (GADD45α) is decreased in radioresistant cervical cancer compared to radiosensitive cancer both in vitro and in vivo. In addition, silencing GADD45α prevents cervical cancer cells from undergoing radiation-induced DNA damage, cell cycle arrest, and a ...[more]

PMID: 29743554

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Project description:Human papillomaviruses (HPV)-related gynecological cancers are a major health care issue, and a leading cause of cancer death in low- and middle-income countries (LMIC). In 2020, the World Health Organization launched a program aimed at cervical cancer elimination, by screening and vaccination strategies. Offering the best possible care to women diagnosed with invasive cancer is a complementary objective. Treatment of cervical cancer as per modern standards is complex and multimodal, mainly relying on surgery, external-beam radiotherapy (+/-chemotherapy) and brachytherapy. In parallel with the pivotal role of multidisciplinary discussion, international societies provide guidance to define the most effective and least toxic anti-cancer strategy, homogenize treatment protocols and provide benchmark quality indicators as a basis for accreditation processes. The challenge is to offer the appropriate diagnostic workup and treatment upfront and to avoid non- evidence-based treatment that consumes resources, impairs quality of life (QoL), and compromises oncological outcome. Various strategies may be applied for improving treatment quality: development of surgical mentorship, companion-training programs and international cooperation. The lack of radiotherapy/brachytherapy facilities is a major concern in LMIC. Reinforcing international support in terms of education, training, research and development and technical cooperation with national projects is required to increase access to minimum requirements but also introduce modern techniques, upgrade radiotherapy/brachytherapy services, and expand access to modern systemic treatments. In countries with robust economies, compliance to standards should also be increased. Integrative cancer care and multidisciplinary approaches are needed to tackle the dual challenge of increasing cure rates while minimizing QoL impairment. Appropriate dimensioning of the resources to avoid harmful treatment delays and access to expert referral centers is also a priority.

Dataset Information

GADD45? sensitizes cervical cancer cells to radiotherapy via increasing cytoplasmic APE1 level.

Publications

GADD45α sensitizes cervical cancer cells to radiotherapy via increasing cytoplasmic APE1 level.

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