PR55α Subunit of Protein Phosphatase 2A Supports the Tumorigenic and Metastatic Potential of Pancreatic Cancer Cells by Sustaining Hyperactive Oncogenic Signaling

Hein, Ashley L.; Seshacharyulu, Parthasarathy; Sheinin, Yuri; Ouellette, Michel; Ponnusamy, Moorthy P.; Mumby, Marc C.; Batra, Surinder K.; Yan, Ying

doi:10.1158/0008-5472.can-15-2119

Cited by 58 publications

(78 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, the hydroxylation in proline 319 by inhibiting this binding favors B55α ubiquitination and degradation. Several reports have highlighted the pro-tumoral activity of B55α (Gilan et al., 2015, Hein et al., 2016, Reid et al., 2013). On the other hand, the role of PHD2 in cancer is more controversial, having shown even opposite effects in different tumor contexts (Chan et al., 2009, Klotzsche-von Ameln et al., 2011).…”

Section: Discussionmentioning

confidence: 99%

PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner

et al. 2017

View full text Add to dashboard Cite

SummaryB55α is a regulatory subunit of the PP2A phosphatase. We have recently found that B55α-associated PP2A promotes partial deactivation of the HIF-prolyl-hydroxylase enzyme PHD2. Here, we show that, in turn, PHD2 triggers degradation of B55α by hydroxylating it at proline 319. In the context of glucose starvation, PHD2 reduces B55α protein levels, which correlates with MDA-MB231 and MCF7 breast cancer cell death. Under these conditions, PHD2 silencing rescues B55α degradation, overcoming apoptosis, whereas in SKBR3 breast cancer cells showing resistance to glucose starvation, B55α knockdown restores cell death and prevents neoplastic growth in vitro. Treatment of MDA-MB231-derived xenografts with the glucose competitor 2-deoxy-glucose leads to tumor regression in the presence of PHD2. Knockdown of PHD2 induces B55α accumulation and treatment resistance by preventing cell apoptosis. Overall, our data unravel B55α as a PHD2 substrate and highlight a role for PHD2-B55α in the response to nutrient deprivation.

show abstract

Section: Discussionmentioning

confidence: 99%

PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The microRNA miR-222 has been shown to support liver cancer cell survival by activating AKT via a mechanism that involves suppression of B55 alpha by the miR [39] . The role for B55 alpha in cells is clearly cell type specific as the B subunit appears to be a tumor promoter in pancreatic cancer [45] . In the study by Hein and colleagues, increased B55 alpha was associated with increased survival signaling including activation of ERK and increased phosphorylation of AKT at serine 473 [45] .…”

Section: B Subunit Proteins As the Drivers Of Pp2a Functionmentioning

confidence: 99%

“…The role for B55 alpha in cells is clearly cell type specific as the B subunit appears to be a tumor promoter in pancreatic cancer [45] . In the study by Hein and colleagues, increased B55 alpha was associated with increased survival signaling including activation of ERK and increased phosphorylation of AKT at serine 473 [45] . The discrepancy between role of the B subunit in pancreatic cancer compared to leukemia and lung cancer likely reflects the composition of the PP2A isoforms in each of these malignant cells.…”

Section: B Subunit Proteins As the Drivers Of Pp2a Functionmentioning

confidence: 99%

The broken “Off” switch in cancer signaling: PP2A as a regulator of tumorigenesis, drug resistance, and immune surveillance

2016

View full text Add to dashboard Cite

Aberrant activation of signal transduction pathways can transform a normal cell to a malignant one and can impart survival properties that render cancer cells resistant to therapy. A diverse set of cascades have been implicated in various cancers including those mediated by serine/threonine kinases such RAS, PI3K/AKT, and PKC. Signal transduction is a dynamic process involving both “On” and “Off” switches. Activating mutations of RAS or PI3K can be viewed as the switch being stuck in the “On” position resulting in continued signaling by a survival and/or proliferation pathway. On the other hand, inactivation of protein phosphatases such as the PP2A family can be seen as the defective “Off” switch that similarly can activate these pathways. A problem for therapeutic targeting of PP2A is that the enzyme is a hetero-trimer and thus drug targeting involves complex structures. More importantly, since PP2A isoforms generally act as tumor suppressors one would want to activate these enzymes rather than suppress them. The elucidation of the role of cellular inhibitors like SET and CIP2A in cancer suggests that targeting these proteins can have therapeutic efficacy by mechanisms involving PP2A activation. Furthermore, drugs such as FTY-720 can activate PP2A isoforms directly. This review will cover the current state of knowledge of PP2A role as a tumor suppressor in cancer cells and as a mediator of processes that can impact drug resistance and immune surveillance.

show abstract

“…A few studies suggest a relationship between pancreatic cancer and PP2A. PP2A promotes pancreatic cancer development by sustaining hyperactivity of multiple oncogenic signaling pathways, including AKT, ERK, and Wnt, and inhibition of PP2A repressed the invasive ability of pancreatic cancer cells . These studies also provide a basis for exploring PP2A as a diagnostic or therapeutic target in pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Glycogen synthase kinase‐3β activity plays a key role in the antitumor effect of nafamostat mesilate in pancreatic cancer cells

Haruki

Shiba

Shimada

et al. 2017

Annals of Gastroent Surgery

View full text Add to dashboard Cite

Pancreatic cancer is often resistant to chemotherapy. We previously showed the efficacy of combination treatment using gemcitabine and nafamostat mesilate (FUT‐175) for patients with unresectable pancreatic cancer. However, the mechanisms that affect the sensitivity of FUT‐175 are not fully understood. The purpose of the present study was to clarify the mechanism of the sensitivity to FUT‐175, with a focus on the activity of glycogen synthase kinase‐3β (GSK‐3β). In vitro, we assessed sensitivity to FUT‐175 in human pancreatic cancer cell lines (PANC‐1 and MIAPaCa‐2) and difference of signaling in these cells by cell proliferation assay, Western blot analysis and microarray. Next, we assessed cell viability, apoptotic signal and nuclear factor‐kappa B (NF‐κB) activity in response to treatment with FUT‐175 alone and in combination with GSK‐3 inhibitor or protein phosphatase 2A (PP2A) by cell proliferation assay, Western blot analysis and enzyme‐linked immunosorbent assay. Phosphorylated GSK‐3β level was significantly higher in MIAPaCa‐2 (high sensitivity cell) than in PANC‐1 (low sensitivity cell). Cell viability and NF‐κB activity were significantly decreased by addition of GSK‐3 inhibitor to FUT‐175, and levels of cleaved caspase‐8 were increased by inhibition of GSK‐3. PP2A inhibitor increased the levels of phosphorylated GSK‐3β and sensitized both cell lines to FUT‐175 as measured by cell viability and apoptotic signal. The results indicate that GSK‐3β activity plays a key role in the antitumor effect of FUT‐175 in pancreatic cancer cells, and regulation of GSK‐3β by PP2A inhibition could be a novel therapeutic approach for pancreatic cancer.

show abstract

PR55α Subunit of Protein Phosphatase 2A Supports the Tumorigenic and Metastatic Potential of Pancreatic Cancer Cells by Sustaining Hyperactive Oncogenic Signaling

Cited by 58 publications

References 45 publications

PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner

PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner

The broken “Off” switch in cancer signaling: PP2A as a regulator of tumorigenesis, drug resistance, and immune surveillance

Glycogen synthase kinase‐3β activity plays a key role in the antitumor effect of nafamostat mesilate in pancreatic cancer cells

Contact Info

Product

Resources

About