An Experimentally Induced Mutation in the UBA Domain of p62 Changes the Sensitivity of Cisplatin by Up-Regulating HK2 Localisation on the Mitochondria and Increasing Mitophagy in A2780 Ovarian Cancer Cells

Yu, Shuyou; Yan, Xiaoyu; Tian, Rui; Xu, Long; Zhao, Yuanxin; Sun, Liankun; Su, Jing

doi:10.3390/ijms22083983

Cited by 9 publications

(7 citation statements)

References 57 publications

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“…Previous studies have shown that the PI3K/AKT pathway plays an important role in glycolysis 38–40 . Moreover, it has been shown that HK2, one of the key metabolic enzymes of glycolysis, plays a crucial role in OC cell proliferation 41–43 . According to these previous studies, our results demonstrated that the ARHGAP10 is a negative regulator in OC cells, which can downregulate the HK2 and the PI3K/AKT pathways.…”

Section: Discussionsupporting

confidence: 78%

SMAD4 inhibits glycolysis in ovarian cancer through PI3K/AKT/HK2 signaling pathway by activating ARHGAP10

Wu,

Gong,

Sun

et al. 2024

Cancer Reports

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BackgroundARHGAP10 is a tumor‐suppressor gene related to ovarian cancer (OC) progression; however, its specific mechanism is unclear.AimsTo investigate the effect of ARHGAP10 on OC cell migration, invasion, and glycolysis.Methods and ResultsQuantitative real‐time PCR (qRT‐PCR) quantified mRNA and protein expressions of AKT, p‐AKT, HK2, and SMAD4 were tested by Western blot. EdU, Wound healing, and Transwell assay were utilized to evaluate OC cell proliferation, migration, and invasion. We used a Seahorse XF24 Extracellular Flux Analyzer to monitor cellular oxygen consumption rates (OCR) and extracellular acidification rates (ECAR). Chromatin immunoprecipitation (ChIP) was used to analyze the transcriptional regulation of ARHGAP10 by SMAD4. ARHGAP10 expression in OC tissues was detected by immunohistochemistry. Our results showed that ARHGAP10 expression was negatively related to lactate levels in human OC tissues. ARHGAP10 overexpression can inhibit the migration, proliferation, and invasion of OC cells, and this function can be blocked by 2‐Deoxy‐D‐glucose. Moreover, we found that ARHGAP10 expression can be rescued with the AKT inhibitor LY294002.ConclusionsThis study revealed that the antitumor effects of ARHGAP10 in vivo and in vitro possibly suppress oncogenic glycolysis through the PI3K/AKT/HK2‐regulated glycolysis metabolism pathway.

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Section: Discussionsupporting

confidence: 78%

SMAD4 inhibits glycolysis in ovarian cancer through PI3K/AKT/HK2 signaling pathway by activating ARHGAP10

Wu,

Gong,

Sun

et al. 2024

Cancer Reports

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“…Mitochondria are involved in the regulation of DDP-induced apoptosis ( Zhang et al, 2021 ), and targeted mitochondria delivery can enhance the toxicity of DDP ( Gao et al, 2021 ; Yu et al, 2021 ). Prior to evaluating the cytotoxicity of TPP-DMON@DDP, we investigated the mitochondrial localization efficiency of nanoplatforms in A2780/DDP cells using confocal laser scanning microscopy (CLSM).…”

Section: Resultsmentioning

confidence: 99%

Mitochondria-Targeted Mesoporous Organic Silica Nanoplatforms for Overcoming Cisplatin Resistance by Disturbing Mitochondrial Redox Homeostasis

Wang

et al. 2022

Front. Chem.

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Cisplatin (also known as DDP) resistance is one of the biggest challenges in the treatment of ovarian cancer. Recent studies have found that mitochondrion, as a potential target of DDP, participates in drug-related apoptosis and resistance. Overexpressed glutathione (GSH) in resistant cells is involved in protecting mitochondria from DDP or DDP-induced ROS. In this work, triphenylphosphonium (TPP) modified disulfide bond-rich (S-S) mesoporous organic silica nanoplatforms (DMON) were developed to deliver DDP (TPP-DMON@DDP) to mitochondria for overcoming DDP resistance. TPP supported the migration of nanoplatforms to the mitochondria, with consequent depletion of mitochondrial GSH by the S-S bond of DMON, leading to mitochondria in redox dyshomeostasis. These treated cells seemed more susceptible to the DDP released from the nanoplatforms. Significantly increased ROS production, mitochondrial damage, and apoptosis were observed in TPP-DMON@DDP-treated cells. Overall, interference of mitochondrial redox homeostasis provides a new opportunity for improving DDP cytotoxicity against resistant cells.

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“…Our previous study showed that p62 is a bridge for Caspase 8 recruitment and activation on the autophagosome membrane in ovarian cancer cells [ 6 ]. Furthermore, mutations in the UBA domain of p62 increased the mitochondrial localization of HK2 and promoted tumor cell survival [ 54 ]. This study verified our hypothesis that p62 promotes the mitochondrial localization of p53 through its UBA domain and that it participates in regulating the sensitivity of ovarian cancer cells to cisplatin.…”

Section: Discussionmentioning

confidence: 99%

p62 Promotes the Mitochondrial Localization of p53 through Its UBA Domain and Participates in Regulating the Sensitivity of Ovarian Cancer Cells to Cisplatin

Kong

Yan

Cheng

et al. 2022

IJMS

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Chemotherapeutic drug-induced p53-dependent crosstalk among tumor cells affects the sensitivity of tumor cells to chemotherapeutic drugs, contributing to chemoresistance. Therefore, pharmacological targeting of p53 may contribute to overcoming drug resistance. The localization of p53 is closely related to its function. Thus, we assessed the effect of p62 on the coordination of p53 mitochondrial localization under chemotherapeutic drug treatment in ovarian cancer cells. We found that the combined use of the proteasome inhibitor epoxomicin and cisplatin led to the accumulation of p53 and sequestosome1(p62) in the mitochondria, downregulated mitochondrial DNA (mtDNA) transcription, inhibited mitochondrial functions, and ultimately promoted apoptosis by enhancing cisplatin sensitivity in ovarian cancer cells. Moreover, the ubiquitin-associated (UBA) domain of p62 was involved in regulating the mitochondrial localization of p53. Our findings suggest that the interaction between p62 and p53 may be a mechanism that determines the fate of tumor cells. In conclusion, p62 coordinated the mitochondrial localization of p53 through its UBA domain, inhibited mtDNA transcription, downregulated mitochondrial function, and promoted ovarian cancer cell death. Our study demonstrates the important role of p53 localization in tumor cell survival and apoptosis, and provides new insights into understanding the anti-tumor mechanism of targeting the ubiquitin–proteasome system in tumor cells

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An Experimentally Induced Mutation in the UBA Domain of p62 Changes the Sensitivity of Cisplatin by Up-Regulating HK2 Localisation on the Mitochondria and Increasing Mitophagy in A2780 Ovarian Cancer Cells

Cited by 9 publications

References 57 publications

SMAD4 inhibits glycolysis in ovarian cancer through PI3K/AKT/HK2 signaling pathway by activating ARHGAP10

SMAD4 inhibits glycolysis in ovarian cancer through PI3K/AKT/HK2 signaling pathway by activating ARHGAP10

Mitochondria-Targeted Mesoporous Organic Silica Nanoplatforms for Overcoming Cisplatin Resistance by Disturbing Mitochondrial Redox Homeostasis

p62 Promotes the Mitochondrial Localization of p53 through Its UBA Domain and Participates in Regulating the Sensitivity of Ovarian Cancer Cells to Cisplatin

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