Non-cell-autonomous Effects of Autophagy Inhibition in Tumor Cells Promote Growth of Drug-resistant Cells

Thorburn, Jacqueline; Staskiewicz, Leah; Goodall, Megan L.; Dimberg, Lina Y.; Frankel, Arthur E.; Ford, Heide L.; Thorburn, Andrew

doi:10.1124/mol.116.106070

Cited by 11 publications

(6 citation statements)

References 34 publications

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“…What are the cellular and cancer contexts in which autophagy inhibition will be therapeutically beneficial [22,394,395,396]? Are there indirect or direct caveats to autophagy inhibition in certain cancer contexts, and how can we minimize them [395,397,398]? Are there clinical and/or molecular tumor features that will allow us to better stratify patients that may benefit from autophagy inhibition in treatment [399,400,401,402]?…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms Underlying Autophagy-Mediated Treatment Resistance in Cancer

Gorski

2019

Cancers

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Despite advances in diagnostic tools and therapeutic options, treatment resistance remains a challenge for many cancer patients. Recent studies have found evidence that autophagy, a cellular pathway that delivers cytoplasmic components to lysosomes for degradation and recycling, contributes to treatment resistance in different cancer types. A role for autophagy in resistance to chemotherapies and targeted therapies has been described based largely on associations with various signaling pathways, including MAPK and PI3K/AKT signaling. However, our current understanding of the molecular mechanisms underlying the role of autophagy in facilitating treatment resistance remains limited. Here we provide a comprehensive summary of the evidence linking autophagy to major signaling pathways in the context of treatment resistance and tumor progression, and then highlight recently emerged molecular mechanisms underlying autophagy and the p62/KEAP1/NRF2 and FOXO3A/PUMA axes in chemoresistance.

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Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms Underlying Autophagy-Mediated Treatment Resistance in Cancer

Gorski

2019

Cancers

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“…Autophagy was firstly linked to tumorigenesis when monoallelic deletion of Beclin1, a modulatory gene on autophagy, was found in breast and ovarian cancers [26]. In contrast, studies have also demonstrated that autophagy inhibition enhanced cytotoxic effects of chemotherapy but promoted proliferation in certain cellular context [27, 28], suggesting that autophagy may play a role in cancer survival under stress. Autophagy provides not only the nutrients and energy but also the cellular restructuring in response to metabolic stress.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of iASPP is required for autophagy in response to oxidative stress in choriocarcinoma

Chan

Wong

et al. 2019

BMC Cancer

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Background Gestational trophoblastic disease (GTD) is a heterogeneous group of diseases developed from trophoblasts. ASPP (Ankyrin-repeat, SH3-domain and proline-rich region containing protein) family proteins, ASPP1 and ASPP2, have been reported to be dysregulated in GTD. They modulate p53 activities and are responsible for multiple cellular processes. Nevertheless, the functional role of the ASPP family inhibitory member, iASPP, is not well characterized in GTD. Methods To study the functional role of iASPP in GTD, trophoblastic tissues from normal placentas, hydatidiform mole (HM) and choriocarcinoma were used for immunohistochemistry, whereas siRNAs were used to manipulate iASPP expression in choriocarcinoma cell lines and study the subsequent molecular changes. Results We demonstrated that iASPP was overexpressed in both HM and choriocarcinoma when compared to normal placenta. Progressive increase in iASPP expression from HM to choriocarcinoma suggests that iASPP may be related to the development of trophoblastic malignancy. High iASPP expression in HM was also significantly associated with a high expression of autophagy-related protein LC3. Interestingly, iASPP silencing retarded the growth of choriocarcinoma through senescence instead of induction of apoptosis. LC3 expression decreased once iASPP was knocked down, suggesting a downregulation on autophagy. This may be due to iASPP downregulation rendered decrease in Atg5 expression and concomitantly hindered autophagy in choriocarcinoma cells. Autophagy inhibition per se had no effect on the growth of choriocarcinoma cells but increased the susceptibility of choriocarcinoma cells to oxidative stress, implying a protective role of iASPP against oxidative stress through autophagy in choriocarcinoma. Conclusions iASPP regulates growth and the cellular responses towards oxidative stress in choriocarcinoma cells. Its overexpression is advantageous to the pathogenesis of GTD. (266 words).

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“…Researchers using clinical samples showed that autophagy was inhibited in patients with high expression of G6PD and ADRB2, or low expression of PTEN and FAT4, contributing to the resistance to lapatinib, 57 sorafenib, 58 trastuzumab 59 and ceritinib, 60 through degradation of HIF1α or promoting epithelial–mesenchymal transition. Additionally, experimental studies also observed that inhibiting autophagy can promote tumor resistance to diphtheria toxin-EGF 61 and sorafenib, 62 by activating caspase and PGE 2 signaling pathways or miR-21 mediated Akt/PTEN signaling pathway. And inhibiting the Akt pathway can activate autophagy to exert autophagy-dependent cell death, thus reversing the acquired resistance.…”

Section: The Important Role Of Autophagy In Tumor Resistancementioning

confidence: 99%

Nanoplatform-Mediated Autophagy Regulation and Combined Anti-Tumor Therapy for Resistant Tumors

Yang,

Ding,

Mao

et al. 2024

IJN

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The overall cancer incidence and death toll have been increasing worldwide. However, the conventional therapies have some obvious limitations, such as non-specific targeting, systemic toxic effects, especially the multidrug resistance (MDR) of tumors, in which, autophagy plays a vital role. Therefore, there is an urgent need for new treatments to reduce adverse reactions, improve the treatment efficacy and expand their therapeutic indications more effectively and accurately. Combination therapy based on autophagy regulators is a very feasible and important method to overcome tumor resistance and sensitize anti-tumor drugs. However, the less improved efficacy, more systemic toxicity and other problems limit its clinical application. Nanotechnology provides a good way to overcome this limitation. Co-delivery of autophagy regulators combined with anti-tumor drugs through nanoplatforms provides a good therapeutic strategy for the treatment of tumors, especially drug-resistant tumors. Notably, the nanomaterials with autophagy regulatory properties have broad therapeutic prospects as carrier platforms, especially in adjuvant therapy. However, further research is still necessary to overcome the difficulties such as the safety, biocompatibility, and side effects of nanomedicine. In addition, clinical research is also indispensable to confirm its application in tumor treatment.

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Non-cell-autonomous Effects of Autophagy Inhibition in Tumor Cells Promote Growth of Drug-resistant Cells

Cited by 11 publications

References 34 publications

Molecular Mechanisms Underlying Autophagy-Mediated Treatment Resistance in Cancer

Molecular Mechanisms Underlying Autophagy-Mediated Treatment Resistance in Cancer

Overexpression of iASPP is required for autophagy in response to oxidative stress in choriocarcinoma

Nanoplatform-Mediated Autophagy Regulation and Combined Anti-Tumor Therapy for Resistant Tumors

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