RSK1 protects P-glycoprotein/ABCB1 against ubiquitin–proteasomal degradation by downregulating the ubiquitin-conjugating enzyme E2 R1

Katayama, Kazuhiro; Fujiwara, Chiaki; Noguchi, Kohji; Sugimoto, Yoshikazu

doi:10.1038/srep36134

Cited by 26 publications

(27 citation statements)

References 39 publications

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“…This may be because RSKs are known to have unidentified, as well as overlapping functions (31). Furthermore, a previous study demonstrated that RSK1 increases ABCB1 expression by suppressing its ubiquitination and proteasomal degradation in human cancer cells (20), which is not consistent with our results. Discrepancies with the previous study might be due to the functional differences of RSKs between mice and humans.…”

Section: Discussioncontrasting

confidence: 99%

MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes

Chelakkot

Liu

Yoshioka

et al. 2020

Preprint

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1The efficacy of aminolevulinic acid (5-ALA)-based photodynamic diagnosis (5-ALA-PDD) and 2 photodynamic therapy (5-ALA-PDT) is dependent on the 5-ALA-induced cancer-specific 3 accumulation of protoporphyrin IX (PpIX). We previously reported that inhibition of oncogenic 4 Ras/MEK increases PpIX accumulation in cancer cells by reducing PpIX efflux through ATP-binding 5 cassette sub-family B member 1 (ABCB1) as well as PpIX conversion to heme by ferrochelatase 6 (FECH). Here, we sought to identify the downstream pathways of Ras/MEK involved in the 7 regulation of PpIX accumulation via ABCB1 and FECH. First, we demonstrated that Ras/MEK 8 activation reduced PpIX accumulation in RasV12-transformed NIH3T3 cells and HRAS transgenic 9 mice. Knockdown of p90 ribosomal S6 kinases (RSK) 2, 3, or 4 increased PpIX accumulation in the 10 RasV12-transformed NIH3T3 cells. Further, treatment with an RSK inhibitor reduced ABCB1 11 expression and increased PpIX accumulation. Moreover, HIF-1α expression was reduced when the 12 RasV12-transformed NIH3T3 cells were treated with a MEK inhibitor, demonstrating that HIF-1α is a 13 downstream element of MEK. HIF-1α inhibition decreased the activity of FECH and increased PpIX 14 accumulation. Finally, we demonstrated the involvement of RSKs and HIF-1α in the regulation of 15 PpIX accumulation in human cancer cell lines (DLD-1, SNB-75, Hs 578T, and MDA MB 231). These 16 results demonstrate that the RSK-ABCB1 and HIF-1α-FECH axes are the downstream pathways of 17 Ras/MEK involved in the regulation of PpIX accumulation. 18 19

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Section: Discussioncontrasting

confidence: 99%

MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes

Chelakkot

Liu

Yoshioka

et al. 2020

Preprint

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“…Although it is less likely that p90RSK is mediating resistance through increased drug efflux given our results in Fig. S2, it could still be possible that p90RSK1 induced upregulation of P-glycoprotein may contribute to the observed resistance via drug efflux as recently describe by Katayama et al (34). These findings not only secure its role in mediating ganetespib resistance in KRAS mutant NSCLC, but also identify p90RSK as a central targetable node to prevent or overcome resistance.…”

Section: Discussionmentioning

confidence: 52%

“…In this current manuscript, we have not identified the key p90RSK substrate(s) that are responsible for inducing resistance to ganetespib; however, we are actively pursuing these targets. p90RSK family has been implicated in the regulation of cell growth and protein synthesis, cell migration and survival, cell proliferation, and cell-cycle progression and in some cases drug efflux (24,33,34). Although it is less likely that p90RSK is mediating resistance through increased drug efflux given our results in Fig.…”

Section: Discussionmentioning

confidence: 99%

Acquired Resistance to the Hsp90 Inhibitor, Ganetespib, inKRAS-Mutant NSCLC Is Mediated via Reactivation of the ERK–p90RSK–mTOR Signaling Network

Chatterjee

Huang

Christie

et al. 2017

Molecular Cancer Therapeutics

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Approximately 25% of non-small cell lung cancer (NSCLC) patients have KRAS mutations and no effective therapeutic strategy exists for these patients. The use of Heat shock protein 90 (Hsp90) inhibitors in KRAS mutant NSCLC appeared to be a promising approach since these inhibitors target many KRAS downstream effectors, however, limited clinical efficacy has been observed due to resistance. Here, we examined the mechanism(s) of acquired resistance to the Hsp90 inhibitor, ganetespib, and identified novel and rationally devised Hsp90 inhibitor combinations which may prevent and overcome resistance to Hsp90 inhibitors. We derived KRAS mutant NSCLC ganetespib resistant (GR) cell lines to identify the resistance mechanism(s) and identified hyperactivation of RAF/MEK/ERK/RSK and PI3K/AKT/mTOR pathways as key resistance mechanisms. Furthermore, we found that GR cells are “addicted” to these pathways as ganetespib resistance lead to synthetic lethality to a dual PI3K/mTOR, a PI3K, or an ERK inhibitor. Interestingly, the levels and activity of a key activator of the mTOR pathway and an ERK downstream target, p90 ribosomal S6 kinase (RSK) were also increased in the GR cells. Genetic or pharmacologic inhibition of p90RSK in GR cells restored sensitivity to ganetespib, whereas p90RSK overexpression induced ganetespib resistance in naïve cells, validating p90RSK as a mediator of resistance and a novel therapeutic target. Our studies offer a way forward for Hsp90 inhibitors through the rational design of Hsp90 inhibitor combinations that may prevent and/or overcome resistance to Hsp90 inhibitors providing an effective therapeutic strategy for KRAS mutant NSCLC.

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“…The role of p38 in cell survival is well documented, and evidence suggests that inhibiting Akt allows p38 to promote cell survival (45,46), which may be the case in our study as we show that BX795 blocks Akt activity. RSK1 also regulates cell survival (47) and down-regulates the ubiquitin-conjugating enzyme E2 R1 (48). ICP0, encoded in the HSV-1 genome, is an E3 ubiquitin ligase that requires the E2 enzyme to perform various roles in HSV-1 infection including the efficient establishment of infection (49).…”

Section: Discussionmentioning

confidence: 99%

An off-target effect of BX795 blocks herpes simplex virus type 1 infection of the eye

et al. 2018

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Herpes simplex virus type 1 (HSV-1) causes recurrent mucocutaneous lesions in the eye that may advance to corneal blindness. Nucleoside analogs exemplified by acyclovir (ACV) form the primary class of antiherpetic drugs, but this class suffers limitations due to the emergence of viral resistance and other side effects. While studying the molecular basis of ocular HSV-1 infection, we observed that BX795, a commonly used inhibitor of TANK-binding kinase 1 (TBK1), strongly suppressed infection by multiple strains of HSV-1 in transformed and primary human cells, cultured human and animal corneas, and a murine model of ocular infection. Our investigations revealed that the antiviral activity of BX795 relies on targeting Akt phosphorylation in infected cells, leading to the blockage of viral protein synthesis. This small-molecule inhibitor, which was also effective against an ACV-resistant HSV-1 strain, shows promise as an alternative to existing drugs and as an effective topical therapy for ocular herpes infection. Collectively, our results obtained using multiple infection models and virus strains establish BX795 as a promising lead compound for broad-spectrum antiviral applications in humans.

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RSK1 protects P-glycoprotein/ABCB1 against ubiquitin–proteasomal degradation by downregulating the ubiquitin-conjugating enzyme E2 R1

Cited by 26 publications

References 39 publications

MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes

MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes

Acquired Resistance to the Hsp90 Inhibitor, Ganetespib, inKRAS-Mutant NSCLC Is Mediated via Reactivation of the ERK–p90RSK–mTOR Signaling Network

An off-target effect of BX795 blocks herpes simplex virus type 1 infection of the eye

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