bims-pimaco 2023-01-01 papers

J Biol Chem. 2022 Dec 26. pii: S0021-9258(22)01285-6. [Epub ahead of print] 102842

Oncogenic RAS promotes MYC protein stability by upregulating the expression of the inhibitor of apoptosis protein (IAP) family member Survivin.

Wen-Hsuan Chang, Yinzhe Liu, Emma A Hammes, Kirsten L Bryant, Richard A Cerione, Marc A Antonyak.

The small GTPase KRAS is frequently mutated in pancreatic cancer and its cooperation with the transcription factor MYC is essential for malignant transformation. The key to oncogenic KRAS and MYC working together is the stabilization of MYC expression due to KRAS activating the extracellular-signal-regulated kinase 1/2 (ERK1/2), which phosphorylates MYC at serine 62 (Ser 62). This prevents the proteasomal degradation of MYC while enhancing its transcriptional activity. Here, we identify how this essential signaling connection between oncogenic KRAS and MYC expression is mediated by the inhibitor of apoptosis protein (IAP) family member Survivin. This discovery stemmed from our finding that Survivin expression is downregulated upon treatment of pancreatic cancer cells with the KRASG12C inhibitor Sotorasib. We went on to show that oncogenic KRAS increases Survivin expression by activating ERK1/2 in pancreatic cancer cells, and that treating the cells either with siRNAs targeting Survivin or with YM155, a small molecule that potently blocks Survivin expression, downregulates MYC and strongly inhibited their growth. We further determined that Survivin protects MYC from degradation by blocking autophagy, which then prevents cellular inhibitor of protein phosphatase 2A (CIP2A) from undergoing autophagic degradation. CIP2A, by inhibiting protein phosphatase 2A (PP2A), helps to maintain MYC phosphorylation at Ser 62, thereby ensuring its cooperation with oncogenic KRAS in driving cancer progression. Overall, these findings highlight a novel role for Survivin in mediating the cooperative actions of KRAS and MYC during malignant transformation and raise the possibility that targeting Survivin may offer therapeutic benefits against KRAS-driven cancers.

Keywords: CIP2A; KRAS; MYC; Pancreatic Cancer; Survivin; and Autophagy

DOI: https://doi.org/10.1016/j.jbc.2022.102842

Bioessays. 2022 Dec 25. e2200196

Control of phosphatidylinositol-3-kinase signaling by nanoscale membrane compartmentalization.

Rebecca Cabral-Dias, Costin N Antonescu.

Phosphatidylinositol-3-kinases (PI3Ks) are lipid kinases that produce 3-phosphorylated derivatives of phosphatidylinositol upon activation by various cues. These 3-phosphorylated lipids bind to various protein effectors to control many cellular functions. Lipid phosphatases such as phosphatase and tensin homolog (PTEN) terminate PI3K-derived signals and are critical to ensure appropriate signaling outcomes. Many lines of evidence indicate that PI3Ks and PTEN, as well as some specific lipid effectors are highly compartmentalized, either in plasma membrane nanodomains or in endosomal compartments. We examine the evidence for specific recruitment of PI3Ks, PTEN, and other related enzymes to membrane nanodomains and endocytic compartments. We then examine the hypothesis that scaffolding of the sources (PI3Ks), terminators (PTEN), and effectors of these lipid signals with a common plasma membrane nanodomain may achieve highly localized lipid signaling and ensure selective activation of specific effectors. This highlights the importance of spatial regulation of PI3K signaling in various physiological and disease contexts.

Keywords: PTEN; SHIP; cell signaling; clathrin; nanodomains; phosphatidylinositol-3-kinase; phosphoinositides

DOI: https://doi.org/10.1002/bies.202200196

Life Sci. 2022 Dec 24. pii: S0024-3205(22)01020-7. [Epub ahead of print] 121320

Enhancement of the antitumor effect of 5-fluorouracil with modulation in drug transporters expression using PI3K inhibitors in colorectal cancer cells.

Sherien M El-Daly, Mahmoud T Abo-Elfadl, Jihan Husseina, Mona A M Abo-Zeid.

AIMS: 5-Fluorouracil (5-FU) represents the cornerstone for colorectal cancer therapy. However, resistance to its action is a major hindrance. This study aimed to investigate the effectiveness of suppressing the activity of PI3K/Akt/mTOR signaling pathway on the chemosensitivity of colorectal cancer cells to 5-FU, as well as to delineate the possible underlying cellular mechanisms and the expected modulation in the expression of specific ABC drug transporters.
MAIN METHODS: HCT116 and Caco-2 cells were incubated with 5-FU, LY294002, or PI-103 individually or in combination. Cell viability was monitored using MTT assay. The expression of a panel of drug transporters was evaluated by RT-PCR. Immunofluorescence staining was applied to evaluate the expression pattern of phospho-AKT, phospho-mTOR, and ABGG2. HPLC evaluated the enhancement in the 5-FU cellular uptake. Cell apoptosis was detected by flow cytometry, and cell morphological changes following treatment were inspected under a fluorescence microscope. Additionally, the migration ability of cells following our suggested treatment combination was examined by wound healing assay.
KEY FINDINGS: The results reveal a notable enhancement in the cytotoxicity of a low dose of 5-FU when combined with a PI3K inhibitor (LY294002 or PI-103). This enhancement was influenced by the significant reduction in the expression of p-AKT and p-mTOR and was also mediated by a significant suppression in the expression of ABCG2 and ABCC5. Consequently, we detected an increase in the cellular uptake and concentration of 5-FU in cells treated with this combination rather than a single 5-FU treatment. Our Suggested combination treatment also induced cell apoptosis and reduced the migration ability of cells.
SIGNIFICANCE: Our data provide evidence that survival signaling pathways represent distinctive targets for the enhancement of chemotherapeutic sensitivity. The antitumor efficacy of 5-FU is enhanced when combined with a PI3K inhibitor, and this effect was mediated by alterations in the expression of specific drug transporters.

Keywords: ABCC5; ABCG2; Apoptosis; Chemosensitivity; LY294002; PI-103

DOI: https://doi.org/10.1016/j.lfs.2022.121320