p62/SQSTM1 is involved in cisplatin resistance in human ovarian cancer cells via the Keap1-Nrf2-ARE system

Xia, Meihui; Yu, Huimei; Gu, Shuang; Xu, Ye; Su, Jing; Li, Hongyan; Kang, Jinsong; Cui, Manhua

doi:10.3892/ijo.2014.2669

Cited by 64 publications

(49 citation statements)

References 27 publications

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“…Second, p62 gene contain an ARE (antioxidant response element) in its promoter, which is a specific Nrf2‐binding site by which Nrf2 induces p62 transcription . Moreover, Nrf2 and p62 were upregulated in some cancers such as liver cancer , gliomas , ovarian cancer , and breast cancer . In this study, we confirmed that Nrf2 and p62 were overexpressed and there was a positive correlation between them in breast cancer tissues and cells.…”

Section: Discussionsupporting

confidence: 71%

PA‐MSHA inhibits the growth of doxorubicin‐resistant MCF‐7/ADR human breast cancer cells by downregulating Nrf2/p62

et al. 2016

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Acquired resistance to doxorubicin in breast cancer is a serious therapeutic problem. In this study, we investigated whether Pseudomonas aeruginosa mannose‐sensitive hemagglutinin (PA‐MSHA) could inhibit the growth of doxorubicin‐resistant breast cancer cells. We found that the expressions of Nrf2 and p62 in breast cancer were higher than that in the corresponding adjacent normal tissues and benign breast epithelial cell. The expressions of Nrf2 and p62 in breast cancer doxorubicin‐resistant cells MCF‐7/ADR were higher than that in doxorubicin‐sensitive cells MCF‐7. Silencing of Nrf2 or p62 rendered breast cancer cells more susceptible to doxorubicin. We further demonstrated that PA‐MSHA inhibited growth and induced apoptosis of MCF‐7/ADR cells but not MCF‐7 cells. Subcutaneous administration of PA‐MSHA greatly inhibited the growth of xenograft tumors from MCF‐7/ADR cells in nude mice. In addition, PA‐MSHA could downregulate Nrf2 and p62 in vitro and in vivo. These results suggested that activation of Nrf2 and p62 was associated with doxorubicin resistance in breast cancer. PA‐MSHA could inhibit the growth of doxorubicin‐resistant MCF‐7/ADR cells and its potential mechanism might be due to the suppression of Nrf2/p62. It indicated the possibility of using PA‐MSHA in doxorubicin‐resistant breast cancer.

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Section: Discussionsupporting

confidence: 71%

PA‐MSHA inhibits the growth of doxorubicin‐resistant MCF‐7/ADR human breast cancer cells by downregulating Nrf2/p62

et al. 2016

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“…The poor outcome associated with high p62 level may be also explained by a pro-survival NF-κB-dependent mechanism that could synergize with autophagy to promote tumor growth 20 . In addition, p62 could activate a protective antioxidant response by engaging the Keap1-Nrf2 signaling pathway and delivers resistance to chemotherapy 45 . Thus, the efficacy of co-targeting p62 in a cetuximab-based regimen warrants future investigation.…”

Section: Discussionmentioning

confidence: 99%

EGFR-targeted mAb therapy modulates autophagy in head and neck squamous cell carcinoma through NLRX1–TUFM protein complex

Lei

Kansy

et al. 2016

Oncogene

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EGFR-targeted therapy in head and neck squamous cell carcinoma (HNSCC) patients frequently results in tumor resistance to treatment. Autophagy is an emerging underlying resistance mechanism, however, the molecular autophagy machinery in HNSCC cells and potential biomarkers of patient response to EGFR-targeted therapy remain insufficiently characterized. Here we show that the EGFR blocking with cetuximab leads to varied autophagic responses, which modulate cancer cell susceptibility to EGFR inhibition. Inhibition of autophagy sensitizes HNSCC cells to EGFR blockade. Importantly, we identify a novel signaling hub centering on the NLRX1-TUFM protein complex, promoting autophagic flux. Defects in the expression of either NLRX1 or TUFM result in compromised autophagy when treated with EGFR inhibitors. As a previously undefined autophagy-promoting mechanism, we found that TUFM serves as a novel anchorage site, recruiting Beclin-1 to mitochondria, promoting its polyubiquitination, and interfering with its interaction with Rubicon. This protein complex is also essential for endoplasmic reticulum (ER) stress signaling induction, possibly as an additional mechanism to promote autophagy. Utilizing tumor specimens from a novel neoadjuvant clinical trial, we show that increased expression of the autophagy adaptor protein, SQSTM1/p62, is associated with poor response to cetuximab therapy. These findings expand our understanding of the components involved in HNSCC autophagy machinery that responds to EGFR inhibitors, and suggest potential combinatorial approaches to enhance its therapeutic efficacy.

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“…36,37 However, recent studies showed that cisplatinresistant ovarian cancer cells express much higher levels of SQSTM1 than do cisplatin-sensitive ovarian cancer cells. 38,39 In addition, the level of SQSTM1 was increased in osteosarcoma cell lines after cisplatin treatment following a temporary decrease at the onset of treatment. 40 Consistent with these studies, the level of SQSTM1 was increased in cisplatin-treated MG-63 cells (Fig.…”

Section: Gfra1 Regulates Autophagy Through Src-ampk Signalingmentioning

confidence: 99%

GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy

et al. 2016

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Recent progress in chemotherapy has significantly increased its efficacy, yet the development of chemoresistance remains a major drawback. In this study, we show that GFRA1/GFRa1 (GDNF family receptor a 1), contributes to cisplatin-induced chemoresistance by regulating autophagy in osteosarcoma. We demonstrate that cisplatin treatment induced GFRA1 expression in human osteosarcoma cells. Induction of GFRA1 expression reduced cisplatin-induced apoptotic cell death and it significantly increased osteosarcoma cell survival via autophagy. GFRA1 regulates AMPK-dependent autophagy by promoting SRC phosphorylation independent of proto-oncogene RET kinase. Cisplatin-resistant osteosarcoma cells showed NFKB1/NFkB-mediated GFRA1 expression. GFRA1 expression promoted tumor formation and growth in mouse xenograft models and inhibition of autophagy in a GFRA1-expressing xenograft mouse model during cisplatin treatment effectively reduced tumor growth and increased survival. In cisplatin-treated patients, treatment period and metastatic status were associated with GFRA1-mediated autophagy. These findings suggest that GFRA1-mediated autophagy is a promising novel target for overcoming cisplatin resistance in osteosarcoma.

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p62/SQSTM1 is involved in cisplatin resistance in human ovarian cancer cells via the Keap1-Nrf2-ARE system

Cited by 64 publications

References 27 publications

PA‐MSHA inhibits the growth of doxorubicin‐resistant MCF‐7/ADR human breast cancer cells by downregulating Nrf2/p62

PA‐MSHA inhibits the growth of doxorubicin‐resistant MCF‐7/ADR human breast cancer cells by downregulating Nrf2/p62

EGFR-targeted mAb therapy modulates autophagy in head and neck squamous cell carcinoma through NLRX1–TUFM protein complex

GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy

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