The two faces of the Integrated Stress Response in cancer progression and therapeutic strategies

Licari, Eugenia; Sánchez‐del‐Campo, Luis; Falletta, Paola

doi:10.1016/j.biocel.2021.106059

Cited by 19 publications

(21 citation statements)

References 112 publications

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“…While this approach involving perturbation of the dynamic metabolic equilibrium of melanoma cells may offer interesting therapeutic opportunities, extreme care is needed in considering the efficacy of this therapeutic strategy. As an example, chemically increasing the ISR pathway could result in more cell death but on the other hand could trigger the metastatic potential of the cells that might enhance disease progression (Licari et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Connecting Metabolic Rewiring With Phenotype Switching in Melanoma

Falletta

Goding

Vivas-García

2022

Front. Cell Dev. Biol.

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Melanoma is a complex and aggressive cancer type that contains different cell subpopulations displaying distinct phenotypes within the same tumor. Metabolic reprogramming, a hallmark of cell transformation, is essential for melanoma cells to adopt different phenotypic states necessary for adaptation to changes arising from a dynamic milieu and oncogenic mutations. Increasing evidence demonstrates how melanoma cells can exhibit distinct metabolic profiles depending on their specific phenotype, allowing adaptation to hostile microenvironmental conditions, such as hypoxia or nutrient depletion. For instance, increased glucose consumption and lipid anabolism are associated with proliferation, while a dependency on exogenous fatty acids and an oxidative state are linked to invasion and metastatic dissemination. How these different metabolic dependencies are integrated with specific cell phenotypes is poorly understood and little is known about metabolic changes underpinning melanoma metastasis. Recent evidence suggests that metabolic rewiring engaging transitions to invasion and metastatic progression may be dependent on several factors, such as specific oncogenic programs or lineage-restricted mechanisms controlling cell metabolism, intra-tumor microenvironmental cues and anatomical location of metastasis. In this review we highlight how the main molecular events supporting melanoma metabolic rewiring and phenotype-switching are parallel and interconnected events that dictate tumor progression and metastatic dissemination through interplay with the tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

Connecting Metabolic Rewiring With Phenotype Switching in Melanoma

Falletta

Goding

Vivas-García

2022

Front. Cell Dev. Biol.

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“…Combining chemotherapies with ISR-targeting agents appears an interesting therapeutic approach to prevent chemoresistance development ( 94 ). One of the most attractive strategies is to hinder the activation of the ISR to suppress the adaptive mechanisms in response to drugs.…”

Section: Translation Regulation By the Integrated Stress Response Pat...mentioning

confidence: 99%

“…However, as the ISR may trigger apoptotic or survival fate in PDA cancer depending on the nature, intensity and duration of the stress, targeting this pathway without complementary cytotoxic drugs remains challenging. This dual role of the ISR is not limited to PDA but extends to many other cancers [for a review, see ( 94 )].…”

Section: Translation Regulation By the Integrated Stress Response Pat...mentioning

confidence: 99%

Translational alterations in pancreatic cancer: a central role for the integrated stress response

et al. 2022

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mRNA translation is a key mechanism for cancer cell proliferation and stress adaptation. Regulation of this machinery implicates upstream pathways such as PI3K/AKT/mTOR, RAS/MEK/ERK and the integrated stress response (ISR), principally coordinating the translation initiation step. During the last decade, dysregulation of the mRNA translation process in pancreatic cancer has been widely reported, and shown to critically impact on cancer initiation, development and survival. This includes translation dysregulation of mRNAs encoding oncogenes and tumor suppressors. Hence, cancer cells survive a stressful microenvironment through a flexible regulation of translation initiation for rapid adaptation. The ISR pathway has an important role in chemoresistance and shows high potential therapeutic interest. Despite the numerous translational alterations reported in pancreatic cancer, their consequences are greatly underestimated. In this review, we summarize the different translation dysregulations described in pancreatic cancer, which make it invulnerable, as well as the latest drug discoveries bringing a glimmer of hope.

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“…Moreover, we and others have shown that autophagy is essential to maintain proteostasis and survival of PCs ( 26 , 27 ). Hence, PCs may benefit from reduced protein synthesis afforded by activation of the ISR that, while reducing global protein synthesis via eIF2α phosphorylation, may enhance ATF4 expression and the downstream activation of pro-survival strategies, including autophagy, antioxidant responses and amino acid metabolism ( 28 , 29 ). Moreover, MM proved resistant to pharmacological inhibition of mTORC1, possibly via induction of the mTORC2/AKT pathway ( 30 , 31 ).…”

Section: Introductionmentioning

confidence: 99%

Preclinical evidence of a direct pro-survival role of arginine deprivation in multiple myeloma

Trudu¹,

Oliva²,

Orfanelli³

et al. 2022

Front. Oncol.

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Multiple myeloma grows by establishing multiple interactions with bone marrow cells. These include expansion of myeloid-derived suppressor cells, which drive immunoevasion via mechanisms that include arginase-1-driven depletion of L-arginine, thus indirectly promoting myeloma cell survival and tumor progression. The peculiar biology of malignant plasma cells postulates that arginine depletion may benefit their fitness also directly, e.g., by engaging the integrated stress response, or by stimulating autophagy through mTORC1 inhibition. We thus investigated the direct impact of arginine deprivation on myeloma cells and challenged its pathophysiological relevance in vitro and in vivo. First, we found that partial arginine depletion spared proliferation of human multiple myeloma cells at concentrations that arrest human T cells. Next, we asked if arginine shortage activates putative adaptive pathways in myeloma cells. Low arginine failed to activate the integrated stress response, as indicated by unmodified phosphorylation of the eukaryotic initiation factor 2α, but sizably inhibited mTORC1, as revealed by reduced phosphorylation of ribosomal protein S6. Notably, depressed mTORC1 activity was not sufficient to increase autophagy, as assessed by the lysosomal digestion rate of the autophagosome-associated protein, LC3-II. Rather, it stimulated mTORC2, resulting in increased phosphatidylinositol-3 kinase-dependent AKT phosphorylation and activity, leading to heightened inhibitory phosphorylation of the pro-apoptotic BAD protein. We then tested whether arginine depletion-activated AKT may protect malignant plasma cells from cell death. Indeed, culturing myeloma cells in low arginine medium significantly reduced the apoptotic effect of the first-in-class proteasome inhibitor, bortezomib, an outcome prevented by pharmacological inhibition of AKT phosphorylation. Finally, we challenged the relevance of the identified circuit in vivo. To gauge the pathophysiologic relevance of low arginine to myeloma growth independently of immunoevasion, we xenotransplanted human myeloma cells subcutaneously into T cell-deficient Rag2–/–γc–/– recipient mice and treated palpable tumor-bearing mice with the clinical-grade arginase inhibitor CB1158. Arginase inhibition significantly raised serum arginine concentration, reduced tumor growth by caliper assessment, and decreased intra-tumor AKT phosphorylation in vivo. Altogether, our results reveal a novel direct pro-survival effect of arginine deprivation on myeloma cells, with potential therapeutic implications.

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The two faces of the Integrated Stress Response in cancer progression and therapeutic strategies

Cited by 19 publications

References 112 publications

Connecting Metabolic Rewiring With Phenotype Switching in Melanoma

Connecting Metabolic Rewiring With Phenotype Switching in Melanoma

Translational alterations in pancreatic cancer: a central role for the integrated stress response

Preclinical evidence of a direct pro-survival role of arginine deprivation in multiple myeloma

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