The role of PAK1 in the sensitivity of kidney epithelial cells to ischemia-like conditions

Zynda, Evan R.; Maloy, Mitchell H; Kandel, Eugene S.

doi:10.1080/15384101.2019.1578149

Cited by 6 publications

(4 citation statements)

References 74 publications

(91 reference statements)

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“…This was observed in two different models of PCa metastasis, representing two different strains of mice, which supports the rigor of our findings. Since PAK1 hyperactivation has also been reported in other diseases, such as osteoarthritis ( 57 ), neurodevelopmental disorders ( 58 ), macrocephaly ( 59 ), intellectual disability ( 60 ), and kidney injury ( 61 ), liposomal IPA3 could have potential therapeutic applications for several non-cancer human diseases.…”

Section: Discussionmentioning

confidence: 99%

Sterically stabilized liposomes targeting P21 (RAC1) activated kinase‑1 and secreted phospholipase A<sub>2</sub> suppress prostate cancer growth and metastasis

et al. 2020

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Metastatic prostate cancer (PCa) has a very high mortality rate in men, in Western countries and lacks reliable treatment. The advanced-stage PCa cells overexpress P21 (RAC1) activated kinase-1 (PAK1) and secreted phospholipase A 2 (sPLA 2) suggesting the potential utility of pharmacologically targeting these molecules to treat metastatic PCa. The small molecule, inhibitor targeting PAK1 activation-3 (IPA3) is a highly specific allosteric inhibitor of PAK1; however, it is metabolically unstable once in the plasma thus, limiting its utility as a chemotherapeutic agent. In the present study, the efficacy and specificity of IPA3 were combined with the stability and the sPLA 2-targeted delivery method of two sterically stabilized liposomes [sterically stabilized long-circulating liposomes (SSL)-IPA3 and sPLA 2 responsive liposomes (SPRL)-IPA3, respectively] to inhibit PCa growth and metastasis. It was found that twice-a-week administration of either SSL-IPA3 or SPRL-IPA3 for 3 weeks effectively suppressed the growth of PC-3 cell tumor xenografts implanted in athymic nude mice. Both drug formulations also inhibited the metastasis of intravenously administered murine RM1 PCa cells to the lungs of C57BL/6 mice. Whereas the twice-a-week administration of SSL-IPA3 significantly inhibited the spontaneous PCa metastasis to the lungs in Transgenic Adenocarcinoma of the Mouse Prostate mice, the administration of free IPA3 had no significant therapeutic benefit. The results present two novel IPA3 encapsulated liposomes to treat metastatic PCa.

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Section: Discussionmentioning

confidence: 99%

Sterically stabilized liposomes targeting P21 (RAC1) activated kinase‑1 and secreted phospholipase A<sub>2</sub> suppress prostate cancer growth and metastasis

et al. 2020

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“…Nevertheless, our observation is not without precedent. There are ample examples of oncogenic factors, which often contribute to tumor growth and survival, decreasing the survival and proliferative potential of cells upon hyperactivation or under specific stress conditions [ 44 , 45 , 46 , 47 ]. In particular, it has been long known that hyperactivity of AKT is stressful, especially to normal cells [ 48 , 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT

Babagana

Brown

Slabodkin

et al. 2021

IJMS

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Hyperactivity of serine-threonine kinase AKT is one of the most common molecular abnormalities in cancer, where it contributes to poor outcomes by facilitating the growth and survival of malignant cells. Despite its well-documented anti-apoptotic effects, hyperactivity of AKT is also known to be stressful to a cell. In an attempt to better elucidate this phenomenon, we observed the signs of proteotoxic stress in cells that harbor hyperactive AKT or have lost its principal negative regulator, PTEN. The activity of HSF1 was predictably elevated under these circumstances. However, such cells proved more sensitive to various regimens of heat shock, including the conditions that were well-tolerated by syngeneic cells without AKT hyperactivity. The sensitizing effect of hyperactive AKT was also seen in HSF1-deficient cells, suggesting that the phenomenon does not require the regulation of HSF1 by this kinase. Notably, the elevated activity of AKT was accompanied by increased levels of XBP1, a key component of cell defense against proteotoxic stress. Interestingly, the cells harboring hyperactive AKT were also more dependent on XBP1 for their growth. Our observations suggest that proteotoxic stress conferred by hyperactive AKT represents a targetable vulnerability, which can be exploited by either elevating the stress above the level tolerated by such cells or by eliminating the factors that enable such tolerance.

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“…Thus, it would be interesting to examine whether the potency of such agents can be improved by concomitant PLK3 inhibition. Furthermore, MAP kinase cascade contributes to some pathophysiological conditions besides cancer . Thus, it would be interesting to explore the merits of PLK3 inhibition in various additional contexts.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, MAP kinase cascade contributes to some pathophysiological conditions besides cancer. 51,52 Thus, it would be interesting to explore the merits of PLK3 inhibition in various additional contexts.…”

Section: Discussionmentioning

confidence: 99%

The role of polo‐like kinase 3 in the response of BRAF‐mutant cells to targeted anticancer therapies

et al. 2019

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The activation of oncogenic mitogen-activated protein kinase cascade via mutations in BRAF is often observed in human melanomas. Targeted inhibitors of BRAF (BRAFi), alone or as a part of a combination therapy, offer a significant benefit to such patients. Unfortunately, some cases are initially nonresponsive to these drugs, while others become refractory in the course of treatment, underscoring the need to understand and mitigate the underlying resistance mechanisms. We report that interference with polo-like kinase 3 (PLK3) reduces the tolerance of BRAF-mutant melanoma cells to BRAFi, while increased PLK3 expression has the opposite effect.Accordingly, PLK3 expression correlates with tolerance to BRAFi in a panel of BRAFmutant cell lines and is elevated in a subset of recurring BRAFi-resistant melanomas.In PLK3-expressing cells, R406, a kinase inhibitor whose targets include PLK3, recapitulates the sensitizing effects of genetic PLK3 inhibitors. The findings support a role for PLK3 as a predictor of BRAFi efficacy and suggest suppression of PLK3 as a way to improve the efficacy of targeted therapy. K E Y W O R D SBRAF, cobimetinib, PLK3, R406, vemurafenib

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The role of PAK1 in the sensitivity of kidney epithelial cells to ischemia-like conditions

Cited by 6 publications

References 74 publications

Sterically stabilized liposomes targeting P21 (RAC1) activated kinase‑1 and secreted phospholipase A<sub>2</sub> suppress prostate cancer growth and metastasis

Sterically stabilized liposomes targeting P21 (RAC1) activated kinase‑1 and secreted phospholipase A<sub>2</sub> suppress prostate cancer growth and metastasis

Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT

The role of polo‐like kinase 3 in the response of BRAF‐mutant cells to targeted anticancer therapies

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