Cancer cells adapt FAM134B/BiP mediated ER-phagy to survive hypoxic stress

Chipurupalli, Sandhya; Ganesan, Raja; Martini, Giulia; Mele, Luigi; Reggio, Alessio; Esposito, Marianna; Elango, K; Namasivayam, Vigneshwaran; Desiderio, Vincenzo; Robinson, Nirmal

doi:10.1038/s41419-022-04813-w

Cited by 28 publications

(28 citation statements)

References 65 publications

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“…These data support the idea that ER-phagy acts as a stress response mechanism that works in concert with the UPR to resolve the stressful condition. Consistently, MCF-7 cells (breast cancer) survive hypoxia induced ER stress by promoting FAM134B mediated ER-phagy ( Chipurupalli et al, 2022 ).…”

Section: Er-phagymentioning

confidence: 96%

Metabolic adaption of cancer cells toward autophagy: Is there a role for ER-phagy?

Gentile

Esposito

2022

Front. Mol. Biosci.

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Autophagy is an evolutionary conserved catabolic pathway that uses a unique double-membrane vesicle, called autophagosome, to sequester cytosolic components, deliver them to lysosomes and recycle amino-acids. Essentially, autophagy acts as a cellular cleaning system that maintains metabolic balance under basal conditions and helps to ensure nutrient viability under stress conditions. It is also an important quality control mechanism that removes misfolded or aggregated proteins and mediates the turnover of damaged and obsolete organelles. In this regard, the idea that autophagy is a non-selective bulk process is outdated. It is now widely accepted that forms of selective autophagy are responsible for metabolic rewiring in response to cellular demand. Given its importance, autophagy plays an essential role during tumorigenesis as it sustains malignant cellular growth by acting as a coping-mechanisms for intracellular and environmental stress that occurs during malignant transformation. Cancer development is accompanied by the formation of a peculiar tumor microenvironment that is mainly characterized by hypoxia (oxygen < 2%) and low nutrient availability. Such conditions challenge cancer cells that must adapt their metabolism to survive. Here we review the regulation of autophagy and selective autophagy by hypoxia and the crosstalk with other stress response mechanisms, such as UPR. Finally, we discuss the emerging role of ER-phagy in sustaining cellular remodeling and quality control during stress conditions that drive tumorigenesis.

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Section: Er-phagymentioning

confidence: 96%

Metabolic adaption of cancer cells toward autophagy: Is there a role for ER-phagy?

Gentile

Esposito

2022

Front. Mol. Biosci.

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“…Interestingly, the small molecule vitexin, a plant-derived flavone O-glycoside, inhibits ER-phagy by disrupting the FAM134B-BIP complex, together with the ability of BIP to chaperone proteins ( Figure 3 ). This double effect of the inhibition of BIP’s folding capacity and of ER-phagy repression suppresses breast cancer growth ( 80 ). Thus, it has been suggested that targeting the FAM134-BIP complex may offer a valid strategy to treat cancer.…”

Section: Er-phagy and Cancermentioning

confidence: 99%

ER stress as a trigger of UPR and ER-phagy in cancer growth and spread

Cherubini¹,

Zito²

2022

Front. Oncol.

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Tumors can survive environmental and metabolic stress by triggering homeostatic responses that re-establish the pre-stress status and permit them to grow and thrive. The endoplasmic reticulum (ER) is the organelle where proteins undergo post-translational modifications and are folded and exported to the secretory pathway. Its environment and activity are therefore fundamental for proteostasis, i.e., the plethora of mechanisms controlling protein formation, folding, degradation, and secretion, needed to assure protein balance and cellular health. In different tumor-related conditions, such as after the activation of oncogenes or under hypoxia and nutrient deprivation, the ER experiences stress, triggered by a high load of proteins to be folded compared to the limited folding capacity of the organelle. As a consequence, three ER membrane sensors and the related unfolded protein response (UPR) are activated. The UPR comprises a complex interconnection between signal transduction pathways that promote a homeostatic response that acts by increasing the amount of protein chaperones and of proteins involved in ER-associated protein degradation (ERAD) on one hand and attenuating protein translation on the other. ER-phagy, literally “eating” the ER, is part of another homeostatic response consisting of the clearance of non-functional ER portions including misfolded proteins. This response is also activated by a set of dedicated ER-phagy receptors after ER stimuli, which overlap the stimuli generating ER stress. Thus, the UPR and ER-phagy are two closely related homeostatic mechanisms that cooperate in re-establishing ER homeostasis. However, while the role of the UPR in favoring cancer growth and thriving by promoting angiogenesis, metastasis, chemotherapy resistance, and epithelial-to-mesenchymal transition is consolidated, that of ER-phagy is still in its infancy. This essay provides an overview of emerging concepts on ER stress, the UPR, and ER-phagy and their crosstalk in tumorigenesis. We also critically review new findings on their pharmacological targeting in cancer.

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“…Apoptosis signal-regulated kinase (ASK1) is a downstream signaling molecule of TRAF2 that activates c-Jun N -terminal protein kinase, which is triggered to maintain ER homeostasis by autophagy [ 97 , 102 ]. Cancer cells survive by inducing p62-dependnt canonical autophagic degradation to overcome ER damage [ 103 ]. For example, ER stress inducers such as TM, brefeldin A, and thapsigargin (TG) activate autophagy in colon and prostate cancer cells, effectively protecting cells against ER stress-induced cell death [ 104 ].…”

Section: Canonical Pathway Regulates Er-stress Responsementioning

confidence: 99%

“…Nevertheless, the loss of ER-phagy receptor FAM123B increases ER stress and reduces cell proliferation in a breast cancer xenograft model [ 103 ]. Limited information on FAM134B necessitates further investigation to identify the precise protective mechanism.…”

Section: Er-specific Autophagymentioning

confidence: 99%

“…Pharmacological ER-phagy receptor regulator vitexin binds with BIP inhibiting ER-phagy and suppressing tumor progression. On the other hand, it acts synergistically with ER stress inducers to slow down cell proliferation [ 103 ]. Further, Hart et al demonstrated the vital role of PERK in autophagy induction, where it enhances the expression levels of c-Myc-induced autophagy by increasing LC3 I/II conversion for autophagosome formation [ 209 ].…”

Section: Maximize the Therapeutic Benefit By Manipulating Er Stress A...mentioning

confidence: 99%

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Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy

Alam

Kabir

Kim

et al. 2022

Cells

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Cancer cells adapt multiple mechanisms to counter intense stress on their way to growth. Tumor microenvironment stress leads to canonical and noncanonical endoplasmic stress (ER) responses, which mediate autophagy and are engaged during proteotoxic challenges to clear unfolded or misfolded proteins and damaged organelles to mitigate stress. In these conditions, autophagy functions as a cytoprotective mechanism in which malignant tumor cells reuse degraded materials to generate energy under adverse growing conditions. However, cellular protection by autophagy is thought to be complicated, contentious, and context-dependent; the stress response to autophagy is suggested to support tumorigenesis and drug resistance, which must be adequately addressed. This review describes significant findings that suggest accelerated autophagy in cancer, a novel obstacle for anticancer therapy, and discusses the UPR components that have been suggested to be untreatable. Thus, addressing the UPR or noncanonical ER stress components is the most effective approach to suppressing cytoprotective autophagy for better and more effective cancer treatment.

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Cancer cells adapt FAM134B/BiP mediated ER-phagy to survive hypoxic stress

Cited by 28 publications

References 65 publications

Metabolic adaption of cancer cells toward autophagy: Is there a role for ER-phagy?

Metabolic adaption of cancer cells toward autophagy: Is there a role for ER-phagy?

ER stress as a trigger of UPR and ER-phagy in cancer growth and spread

Canonical and Noncanonical ER Stress-Mediated Autophagy Is a Bite the Bullet in View of Cancer Therapy

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