ERK is a Pivotal Player of Chemo-Immune-Resistance in Cancer

Salaroglio, Iris C.; Mungo, Eleonora; Gazzano, Elena; Kopecka, Joanna; Riganti, Chiara

doi:10.3390/ijms20102505

Cited by 102 publications

(79 citation statements)

References 185 publications

(273 reference statements)

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“…Upon binding of its ligand Wnt5a, ROR1 recruits Src, CK1ε and Rab GTPases leading to downstream activation of the MAPK/ERK and P13K/AKT growth pathways 22,30,31 . Both P13K/AKT MAPK/ERK have been shown to be highly activated in chemoresistant malignancies where they promote tumor persistence by inhibiting drug-induced apoptosis 32,33 . Interestingly, activation of the MAPK/ERK pathway also inhibits proteasomal degradation of ABCB1 via downregulation of UBE2R1, a member of the UPS system 20 .…”

Section: Discussionmentioning

confidence: 99%

ROR1 regulates chemoresistance in Breast Cancer via modulation of drug efflux pump ABCB1

Fultang

Illendula

Lin

et al. 2020

Sci Rep

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Chemoresistance is one of the leading causes of mortality in breast cancer (BC). Understanding the molecules regulating chemoresistance is critical in order to combat chemoresistant BC. Drug efflux pump ABCB1 is overexpressed in chemoresistant neoplasms where it effluxes various chemotherapeutic agents from cells. Because it is expressed in normal and cancerous cells alike, attempts at targeting ABCB1 directly have failed due to low specificity and disruption of normal tissue. A proposed method to inhibit ABCB1 is to target its cancer-specific, upstream regulators, mitigating damage to normal tissue. Few such cancer-specific upstream regulators have been described. Here we characterize ROR1 as an upstream regulator of ABCB1. ROR1 is highly expressed during development but not expressed in normal adult tissue. It is however highly expressed in several cancers. ROR1 is overexpressed in chemoresistant BC where it correlates with poor therapy response and tumor recurrence. Our data suggests, ROR1 inhibition sensitizes BC cells to chemo drugs. We also show ROR1 regulates ABCB1 stability and transcription via MAPK/ERK and p53. Validating our overall findings, inhibition of ROR1 directly correlated with decreased efflux of chemo-drugs from cells. Overall, our results highlight ROR1's potential as a therapeutic target for multidrug resistant malignancies. ROR1 knockdown potentiates DNA damage induced by chemo drugs.A mechanism of action common to both Pt-based and anthracycline chemotherapeutic agents is induction of DNA double stranded breaks leading to cell death 19 . We thus sought to investigate if ROR1 inhibition would promote chemo-induced DNA double strand breaks. We treated cells transfected with either ROR1 siRNA or control RNA, with Doxorubicin or Cisplatin, and monitored γH2a.x, a marker for DNA double strand breaks via immunofluorescence ( Fig. 3A, Supplementary Fig. 2). We observed potentiation of DNA double strand breaks induced by both drugs in cells where ROR1 was knocked down. γH2a.x foci counts were higher in the siROR1+ (Dox or Cis) groups compared to the siROR1-only and drug-only treatment groups (Fig. 3B). We similarly observed an increase in γH2a.x expression (mean fluorescence intensity) in Cis/Dox treated cells after ROR1 knockdown compared to the control group (Fig. 3C). Altogether, these data suggest ROR1 inhibition promotes chemo drug-induced DNA damage. Scientific RepoRtS |(2020) 10:1821 | https://doi.

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Section: Discussionmentioning

confidence: 99%

ROR1 regulates chemoresistance in Breast Cancer via modulation of drug efflux pump ABCB1

Fultang

Illendula

Lin

et al. 2020

Sci Rep

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“…Aside from enforcing KRAS autocrine signaling, the IRAK4/ TPL2 axis is further used following genotoxic stress as a survival mechanism. Induction of MAPK activity is a well-established mechanism that allows cancer cells to endure genotoxic stress (48). However, MEK inhibitors fail to potentiate chemotherapy in pancreatic cancer (49,50), suggesting that targeting MAPK alone is insufficient, or that compensatory escape mechanisms such as enhanced NF-κB activity should be cotargeted.…”

Section: R E S E a R C H A R T I C L Ementioning

confidence: 99%

TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations

Dodhiawala¹,

Khurana²,

Zhang³

et al. 2020

Journal of Clinical Investigation

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“…5 and s7). Because ERK activation has roles in both pro-and anti-inflammatory actions of microglia [59][60][61], we also examined the effect on cAMP response element-binding protein (CREB), which participates in the anti-inflammatory actions [62]. However, no effect in CREB level or phosphorylation was observed ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Immunoregulation of microglial polarization: an unrecognized physiological function of α-synuclein

Stewart

Sheng

et al. 2020

J Neuroinflammation

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Background Microglial function is vital for maintaining the health of the brain, and their activation is an essential component of neurodegeneration. There is significant research on factors that provoke “reactive” or “inflammatory” phenotypes in conditions of injury or disease. One such factor, exposure to the aggregated or oligomeric forms of α-synuclein, an abundant brain protein, plays an essential role in driving microglial activation; including chemotactic migration and production of inflammatory mediators in Lewy body (LB) diseases such as Parkinson’s disease. On the other hand, it is increasingly recognized that microglia also undergo changes, dependent on the cellular environment, that promote mainly reconstructive and anti-inflammatory functions, i.e., mostly desirable functions of microglia in a physiological state. What maintains microglia in this physiological state is essentially unknown. Methods In this study, using in vitro and in vivo models, we challenged primary microglia or BV2 microglia with LPS + IFN-γ, IL-4 + IL-13, α-synuclein monomer, and α-synuclein oligomer, and examined microglia phenotype and the underlying mechanism by RT-PCR, Western blot, ELISA, IF, IHC, Co-IP. Results We described a novel physiological function of α-synuclein, in which it modulates microglia toward an anti-inflammatory phenotype by interaction with extracellular signal-regulated kinase (ERK) and recruitment of the ERK, nuclear factor kappa B (NF-κB), and peroxisome proliferator-activated receptor γ (PPARγ) pathways. Conclusions These findings suggest a previously unrecognized function of monomeric α-synuclein that likely gives new insights into the pathogenesis and potential therapies for Lewy body-related diseases and beyond, given the abundance and multiple functions of α-synuclein in brain tissue.

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ERK is a Pivotal Player of Chemo-Immune-Resistance in Cancer

Cited by 102 publications

References 185 publications

ROR1 regulates chemoresistance in Breast Cancer via modulation of drug efflux pump ABCB1

ROR1 regulates chemoresistance in Breast Cancer via modulation of drug efflux pump ABCB1

TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations

Immunoregulation of microglial polarization: an unrecognized physiological function of α-synuclein

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