HSP90AA1-mediated autophagy promotes drug resistance in osteosarcoma

Xiao, Xin; Wang, Wei; Li, Yuqian; Yang, Di; Li, Xiaokang; Shen, Chao; Liu, Yan; Ke, Xia; Guo, Shuo; Guo, Zheng

doi:10.1186/s13046-018-0880-6

Cited by 210 publications

(150 citation statements)

References 46 publications

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“…Both Akt/mTOR and ERK1/2 axes mediate cell proliferation, migration, and inhibition of apoptosis in osteosarcoma [43][44][45]. As far as drug resistance is concerned, Akt/mTOR induces resistance to doxorubicin, cisplatin, and methotrexate by promoting pro-survival autophagy [46]. Consistently, Everolimus has been proposed as a second-line treatment in osteosarcoma: unluckily, it did not achieve a complete response in patient-derived doxorubicin-resistant osteosarcoma xenografts [47] or in patients with high-grade relapsed osteosarcoma [48] when used alone.…”

Section: Discussionmentioning

confidence: 99%

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

Belisario

Akman

Godel

et al. 2020

Cells

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The ATP Binding Cassette transporter B1 (ABCB1) induces chemoresistance in osteosarcoma, because it effluxes doxorubicin, reducing the intracellular accumulation, toxicity, and immunogenic cell death induced by the drug. The ATP Binding Cassette transporter A1 (ABCA1) effluxes isopentenyl pyrophosphate (IPP), a strong activator of anti-tumor Vγ9Vδ2 T-cells. Recruiting this population may represent an alternative strategy to rescue doxorubicin efficacy in ABCB1-expressing osteosarcoma. In this work, we analyzed how ABCA1 and ABCB1 are regulated in osteosarcoma, and if increasing the ABCA1-dependent activation of Vγ9Vδ2 T-cells could be an effective strategy against ABCB1-expressing osteosarcoma. We used 2D-cultured doxorubicin-sensitive human U-2OS and Saos-2 cells, their doxorubicin-resistant sublines (U-2OS/DX580 and Saos-2/DX580), and 3D cultures of U-2OS and Saos-2 cells. DX580-sublines and 3D cultures had higher levels of ABCB1 and higher resistance to doxorubicin than parental cells. Surprisingly, they had reduced ABCA1 levels, IPP efflux, and Vγ9Vδ2 T-cell-induced killing. In these chemo-immune-resistant cells, the Ras/Akt/mTOR axis inhibits the ABCA1-transcription induced by Liver X Receptor α (LXRα); Ras/ERK1/2/HIF-1α axis up-regulates ABCB1. Targeting the farnesylation of Ras with self-assembling nanoparticles encapsulating zoledronic acid (NZ) simultaneously inhibited both axes. In humanized mice, NZ reduced the growth of chemo-immune-resistant osteosarcomas, increased intratumor necro-apoptosis, and ABCA1/ABCB1 ratio and Vγ9Vδ2 T-cell infiltration. We suggest that the ABCB1 high ABCA1 low phenotype is indicative of chemo-immune-resistance. We propose aminobisphosphonates as new chemo-immune-sensitizing tools against drug-resistant osteosarcomas.

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Section: Discussionmentioning

confidence: 99%

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

Belisario

Akman

Godel

et al. 2020

Cells

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“…It can be associated with cell death, leading to the activation of the pro-death signaling pathway in cancer cells [34]. In other circumstances, autophagy can be cytoprotective, promoting cell survival, resistance to anticancer treatments, and protection from apoptosis [38,39]. In this latter case, inhibition of autophagy was shown to increase cell death in various cancer cell types in response to anticancer drugs, whether synthetic or of natural origin [39,40].…”

Section: Discussionmentioning

confidence: 99%

Origanum majorana Essential Oil Triggers p38 MAPK-Mediated Protective Autophagy, Apoptosis, and Caspase-Dependent Cleavage of P70S6K in Colorectal Cancer Cells

et al. 2020

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Colorectal cancer (CRC) is the third most common type of cancer in terms of incidence and mortality worldwide. Here we have investigated the anti-colon cancer potential of Origanum majorana essential oil (OMEO) and its underlying mechanisms of action. We showed that OMEO significantly inhibited the cellular viability and colony growth of human HT-29 colorectal cancer cells. OMEO induced protective autophagy, associated with downregulation of the mTOR/p70S6K pathway, and activated caspase-8 and caspase-9-dependent apoptosis. Blockade of autophagy with 3-methyladenine (3-MA) and chloroquine (CQ), two autophagy inhibitors, potentiated the OMEO-induced apoptotic cell death. Inversely, inhibition of apoptosis with the pan-caspase inhibitor, Z-VAD-FMK, significantly reduced cell death, suggesting that apoptosis represents the main mechanism of OMEO-induced cell death. Mechanistically, we found that OMEO induces protective autophagy and apoptotic cells death via the activation of the p38 MAPK signaling pathway. Pharmacological inhibition of p38 MAPK by the p38 inhibitors SB 202190 and SB 203580 not only significantly decreased apoptotic cell death, but also reduced the autophagy level in OMEO treated HT-29 cells. Strikingly, we found that OMEO also induces p38 MAPK-mediated caspase-dependent cleavage of p70S6K, a protein reported to be overexpressed in colon cancer and associated with drug resistance. Our findings suggest that OMEO inhibits colon cancer through p38 MAPK-mediated protective autophagy and apoptosis associated with caspase-dependent cleavage of p70S6K. To the best of our knowledge, this study is the first to report on the implications of the p38 MAPK signaling pathway in targeting p70S6K to caspase cleavage.

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“…In drug-resistant MCF-7 cells, autophagy inhibition was able to re-sensitise cells to treatment [94] . Finally, three common chemotherapeutics used in the treatment of osteosarcoma induced upregulation of HSP90AA1, which was shown to be a regulator of autophagy via PI3K/Akt/mTOR and apoptosis via JNK/p38 [95] . Understanding the crosstalk of these pathways in the context of drug resistance will be critical in the development of new therapies.…”

Section: Autophagy and Drug Resistancementioning

confidence: 99%

The importance of epithelial-mesenchymal transition and autophagy in cancer drug resistance

Hill¹,

Wang²

2019

CDR

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Epithelial-mesenchymal transition (EMT) and autophagy are both known to play important roles in the development of cancer. Subsequently, these processes are now being utilised as targets for therapy. Cancer is globally one of the leading causes of death, and, despite many advances in treatment options, patients still face many challenges. Drug resistance in cancer-therapy is a large problem, and both EMT and autophagy have been shown to contribute. However, given the context-dependent role of these processes and the complexity of the interactions between them, elucidating how they both act alone and interact is important. In this review, we provide insight into the current landscape of the interactions of autophagy and EMT in the context of malignancy, and how this ultimately may affect drug resistance in cancer therapy.

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HSP90AA1-mediated autophagy promotes drug resistance in osteosarcoma

Cited by 210 publications

References 46 publications

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

Origanum majorana Essential Oil Triggers p38 MAPK-Mediated Protective Autophagy, Apoptosis, and Caspase-Dependent Cleavage of P70S6K in Colorectal Cancer Cells

The importance of epithelial-mesenchymal transition and autophagy in cancer drug resistance

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