Targetome analysis of chaperone-mediated autophagy in cancer cells

Hao, Yuqing; Kacal, Merve; Ouchida, Amanda Tomie; Zhang, Boxi; Norberg, Erik; Vakifahmetoglu-Norberg, Helin

doi:10.1080/15548627.2019.1586255

Cited by 65 publications

(58 citation statements)

References 41 publications

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“…CMA plays an important role under hypoxia conditions in the regulation of the tumor metabolism by degrading cell cycle regulatory proteins such as phosphorylated serine/threonine-protein kinase (CHK1) [111] and hypoxia-inducible factor 1α (HIF1α) [112,113]. In addition, quantitative proteomics analysis of isolated lysosomes from CMA-activated conditions in cancer cells has recently revealed a new role for CMA in the control of cell translation [114]. Importantly, up-regulated CMA may also assist chemoresistance of GB, making them more resistant to different stressors such as oxidative stress, hypoxia or even DNA damage agents [4,115].…”

Section: Functionsmentioning

confidence: 99%

Autophagy in the Immunosuppressive Perivascular Microenvironment of Glioblastoma

Molina

García‐Bernal

Valdor

2019

Cancers

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Glioblastoma (GB) has been shown to up-regulate autophagy with anti- or pro-oncogenic effects. Recently, our group has shown how GB cells aberrantly up-regulate chaperone-mediated autophagy (CMA) in pericytes of peritumoral areas to modulate their immune function through cell-cell interaction and in the tumor’s own benefit. Thus, to understand GB progression, the effect that GB cells could have on autophagy of immune cells that surround the tumor needs to be deeply explored. In this review, we summarize all the latest evidence of several molecular and cellular immunosuppressive mechanisms in the perivascular tumor microenvironment. This immunosuppression has been reported to facilitate GB progression and may be differently modulated by several types of autophagy as a critical point to be considered for therapeutic interventions.

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Section: Functionsmentioning

confidence: 99%

Autophagy in the Immunosuppressive Perivascular Microenvironment of Glioblastoma

Molina

García‐Bernal

Valdor

2019

Cancers

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“…Because the classical lysosome-mediated macroautophagy is regulated by mTORC1, we searched for a new mTORC2-dependent mechanism that may account for lysosomal degradation of TF. We found that mTORC2 is involved in suppression of the chaperone mediated autophagy (CMA) ( 29 ), which specifically target substrate proteins containing the KFERQ-like loop motif ( 30 , 31 ). We therefore employed Pymol software to construct TF protein homology model.…”

Section: Resultsmentioning

confidence: 99%

mTOR Promotes Tissue Factor Expression and Activity in EGFR-Mutant Cancer

Cong

Zhang

et al. 2020

Front. Oncol.

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Mechanistic target of rapamycin (mTOR) signaling pathway mediates the function of oncogenic receptor tyrosine kinases (RTKs). We aimed to elucidate new role of mTOR in EGFR-mutant (EGFR-mut) non-small cell lung cancer (NSCLC) and glioblastoma (GBM) with a focus on tumor microenvironments. Here, we report a novel regulatory link between mTOR complexes (mTORCs) and tissue factor (TF), an initiator of tumorderived thrombosis. TF is elevated in EGFR-mut NSCLC/GBM cell lines and tumors from patients with poor prognosis. Application of mTORC1/2 inhibitors (AZD8055, WYE-125132, MTI-31, and rapamycin) or genetic mTORC-depletion all reduced TF expression, which appeared to be differentially mediated depending on cellular context. In U87MG and HCC827 cells, mTORC1 exerted a dominant role via promoting TF mRNA transcription. In EGFR-TKI-resistant H1975 and PC9 cells, it was mTORC2 that played a major role in specific repression of lysosomal-targeted TF protein degradation. Successful inhibition of TF expression was demonstrated in AZD8055-or MTI-31treated H1975 and U87MG tumors in mice, while a TF-targeted antibody antagonized TF activity without reducing TF protein. Both the mTOR-and TF-targeted therapy induced a multifaceted remodeling of tumor microenvironment reflecting not only a diminished hypercoagulopathy state (fibrin level) but also a reduced stromal fibrosis (collagen distribution), compromised vessel density and/or maturity (CD31 and/or α-SMA) as well as a substantially decreased infiltration of immune-suppressive M2-type tumor-associated macrophages (CD206/F4/80 ratio). Thus, our results have identified TF as a functional biomarker of mTOR. Downregulation of mTOR-TF axis activity likely contributes to the therapeutic mechanism of mTORC1/2-and TF-targeted agents in EGFR-mut advanced NSCLC and GBM.

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“…Very recently, a quantitative multiplex analysis of CMA substrates performed in a wide range of cancer cell lines identified more than 250 putative new CMA substrates [48]. This was performed in a condition where CMA was inhibited through the expression of a highly specific LAMP2A siRNA in order to specifically inhibit CMA without directly affecting MA.…”

Section: Chaperone-mediated Autophagy (Cma)mentioning

confidence: 99%

Chaperone-Mediated Autophagy and Its Emerging Role in Hematological Malignancies

Robert

Jacquel

Auberger

2019

Cells

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Chaperone-mediated autophagy (CMA) ensures the selective degradation of cellular proteins endowed with a KFERQ-like motif by lysosomes. It is estimated that 30% of all cellular proteins can be directed to the lysosome for CMA degradation, but only a few substrates have been formally identified so far. Mechanistically, the KFERQ-like motifs present in substrate proteins are recognized by the molecular chaperone Hsc70c (Heat shock cognate 71 kDa protein cytosolic), also known as HSPA8, and directed to LAMP2A, which acts as the CMA receptor at the lysosomal surface. Following linearization, the protein substrate is next transported to the lumen of the lysosomes, where it is degraded by resident proteases, mainly cathepsins and eventually recycled to sustain cellular homeostasis. CMA is induced by different stress conditions, including energy deprivation that also activates macro-autophagy (MA), that may make it difficult to decipher the relative impact of both pathways on cellular homeostasis. Besides common inducing triggers, CMA and MA might be induced as compensatory mechanisms when either mechanism is altered, as it is the often the case in different pathological settings. Therefore, CMA activation can compensate for alterations of MA and vice versa. In this context, these compensatory mechanisms, when occurring, may be targeted for therapeutic purposes. Both processes have received particular attention from scientists and clinicians, since modulation of MA and CMA may have a profound impact on cellular proteostasis, metabolism, death, differentiation, and survival and, as such, could be targeted for therapeutic intervention in degenerative and immune diseases, as well as in cancer, including hematopoietic malignancies. The role of MA in cancer initiation and progression is now well established, but whether and how CMA is involved in tumorigenesis has been only sparsely explored. In the present review, we encompass the description of the mechanisms involved in CMA, its function in the physiology and pathogenesis of hematopoietic cells, its emerging role in cancer initiation and development, and, finally, the potential therapeutic opportunity to target CMA or CMA-mediated compensatory mechanisms in hematological malignancies.

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Targetome analysis of chaperone-mediated autophagy in cancer cells

Cited by 65 publications

References 41 publications

Autophagy in the Immunosuppressive Perivascular Microenvironment of Glioblastoma

Autophagy in the Immunosuppressive Perivascular Microenvironment of Glioblastoma

mTOR Promotes Tissue Factor Expression and Activity in EGFR-Mutant Cancer

Chaperone-Mediated Autophagy and Its Emerging Role in Hematological Malignancies

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