PT109, a novel multi-kinase inhibitor suppresses glioblastoma multiforme through cell reprogramming: Involvement of PTBP1/PKM1/2 pathway

Yang, Yang; Tu, Yalin; Lu, Junfeng; Chen, Qiuhe; Zhu, Zhaowen; Peng, Weijia; Zhu, Wenbo; Wen, Shijun; Zhang, Ji; Yin, Wei

doi:10.1016/j.ejphar.2022.174837

Cited by 9 publications

(4 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While PKM1 is a highly active isoform, most cancers expressed PKM2 rather than PKM1 to promote Warburg's effect. The increased PKM1 level in HLCS knockdown could attenuate cancer growth, as reported in prostate adenocarcinoma, where inhibiting receptor tyrosine kinase signaling induces the expression of PKM1 and attenuates the growth of glioblastoma (Yang et al, 2022). The tumor suppressor role of PKM1 was also reported in breast cancer (Choksi et al, 2021) and prostate adenocarcinoma (Davidson et al, 2022).…”

Section: Holocarboxylase Synthetase Suppression Perturbs the Expressi...mentioning

confidence: 69%

Proteomic analysis of holocarboxylase synthetase deficient-MDA-MB-231 breast cancer cells revealed the biochemical changes associated with cell death, impaired growth signaling, and metabolism

Sukjoi,

Young,

Acland

et al. 2024

Front. Mol. Biosci.

View full text Add to dashboard Cite

We have previously shown that the holocarboxylase synthetase (HLCS) is overexpressed in breast cancer tissue of patients, and silencing of its expression in triple-negative cancer cell line inhibits growth and migration. Here we investigated the global biochemical changes associated with HLCS knockdown in MDA-MB-231 cells to discern the pathways that involve HLCS. Proteomic analysis of two independent HLCS knockdown cell lines identified 347 differentially expressed proteins (DEPs) whose expression change > 2-fold (p < 0.05) relative to the control cell line. GO enrichment analysis showed that these DEPs were mainly associated with the cellular process such as cellular metabolic process, cellular response to stimulus, and cellular component organization or biogenesis, metabolic process, biological regulation, response to stimuli, localization, and signaling. Among the 347 identified DEPs, 64 proteins were commonly found in both HLCS knockdown clones, confirming their authenticity. Validation of some of these DEPs by Western blot analysis showed that plasminogen activator inhibitor type 2 (SerpinB2) and interstitial collagenase (MMP1) were approximately 90% decreased in HLCS knockdown cells, consistent with a 50%–60% decrease in invasion ability of knockdown cells. Notably, argininosuccinate synthase 1 (ASS1), one of the enzymes in the urea cycle, showed approximately a 10-fold increase in the knockdown cells, suggesting the crucial role of HLCS in supporting the urea cycle in the triple-negative cancer cell line. Collectively, our proteomic data provide biochemical insights into how suppression of HLCS expression perturbs global changes in cellular processes and metabolic pathways, impairing cell growth and invasion.

show abstract

Section: Holocarboxylase Synthetase Suppression Perturbs the Expressi...mentioning

confidence: 69%

Proteomic analysis of holocarboxylase synthetase deficient-MDA-MB-231 breast cancer cells revealed the biochemical changes associated with cell death, impaired growth signaling, and metabolism

Sukjoi,

Young,

Acland

et al. 2024

Front. Mol. Biosci.

View full text Add to dashboard Cite

show abstract

“…The terms transdifferentiation and direct reprogramming or direct conversion have also been used in contexts where one type of stem cell or glial cell is converted into a completely different type of stem cell or glial cell [ 33 , 51 ]. Previous studies showed that transformation agents such as histone deacetylase inhibitors, multi-kinase inhibitors, and bone morphogenetic proteins (BMPs) can revert GBM cells to their glial origins or to other glial cell types such as oligodendrocytes [ 32 , 52 , 53 , 54 , 55 , 56 ]. Reprogramming was applied to convert GBM cells into astrocytes and mesenchymal cells [ 52 , 57 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

Reprogramming Glioblastoma Cells into Non-Cancerous Neuronal Cells as a Novel Anti-Cancer Strategy

Jiang,

Yu,

Estaba

et al. 2024

Cells

View full text Add to dashboard Cite

Glioblastoma Multiforme (GBM) is an aggressive brain tumor with a high mortality rate. Direct reprogramming of glial cells to different cell lineages, such as induced neural stem cells (iNSCs) and induced neurons (iNeurons), provides genetic tools to manipulate a cell’s fate as a potential therapy for neurological diseases. NeuroD1 (ND1) is a master transcriptional factor for neurogenesis and it promotes neuronal differentiation. In the present study, we tested the hypothesis that the expression of ND1 in GBM cells can force them to differentiate toward post-mitotic neurons and halt GBM tumor progression. In cultured human GBM cell lines, including LN229, U87, and U373 as temozolomide (TMZ)-sensitive and T98G as TMZ-resistant cells, the neuronal lineage conversion was induced by an adeno-associated virus (AAV) package carrying ND1. Twenty-one days after AAV-ND1 transduction, ND1-expressing cells displayed neuronal markers MAP2, TUJ1, and NeuN. The ND1-induced transdifferentiation was regulated by Wnt signaling and markedly enhanced under a hypoxic condition (2% O2 vs. 21% O2). ND1-expressing GBM cultures had fewer BrdU-positive proliferating cells compared to vector control cultures. Increased cell death was visualized by TUNEL staining, and reduced migrative activity was demonstrated in the wound-healing test after ND1 reprogramming in both TMZ-sensitive and -resistant GBM cells. In a striking contrast to cancer cells, converted cells expressed the anti-tumor gene p53. In an orthotopical GBM mouse model, AAV-ND1-reprogrammed U373 cells were transplanted into the fornix of the cyclosporine-immunocompromised C57BL/6 mouse brain. Compared to control GBM cell-formed tumors, cells from ND1-reprogrammed cultures formed smaller tumors and expressed neuronal markers such as TUJ1 in the brain. Thus, reprogramming using a single-factor ND1 overcame drug resistance, converting malignant cells of heterogeneous GBM cells to normal neuron-like cells in vitro and in vivo. These novel observations warrant further research using patient-derived GBM cells and patient-derived xenograft (PDX) models as a potentially effective treatment for a deadly brain cancer and likely other astrocytoma tumors.

show abstract

“…Glial-to-neuronal conversion by CasRx-mediated Ptbp1 knockdown represents a promising in vivo genetic approach for the treatment of various diseases caused by neuronal deficiency [48]. In the field of oncology research, PT109, a novel multikinase inhibitor, reprogrammes glioblastoma multiforme (GBM) into oligodendrocytes by decreasing the level of PTBP1 and increasing the ratio of pyruvate kinase M1/2 (PKM1/2), and alters the metabolic pattern of GBM via the PTBP1/PKM1/2 pathway [49].…”

Section: Discussionmentioning

confidence: 99%

PTBP1 drives c-Myc-dependent gastric cancer progression and stemness

Chu

et al. 2023

Br J Cancer

View full text Add to dashboard Cite

Background Gastric cancer (GC) tumorigenesis and treatment failure are caused by cancer stem cells. Polypyrimidine tract binding protein 1 (PTBP1) was shown to be involved in the development of embryonic stem cells and is now being considered as a therapeutic target for tumour progression and stem-cell characteristics. Methods PTBP1 expression in GC samples was detected using tissue microarrays. Proliferation, colony formation, spheroid formation and stem-cell analysis were used to examine PTBP1’s role in tumorigenesis and stem-cell maintenance. In AGS and HGC-27 cells with or without PTBP1 deficiency, ubiquitin-related protein expression and co-precipitation assays were performed. Results We identified that PTBP1 was aberrantly highly expressed and represented a novel prognostic factor in GC patients. PTBP1 maintained the tumorigenic activity and stem-cell characteristics of GC in vitro and in vivo. PTBP1 directly interacts with c-Myc and stabilises its protein levels by preventing its proteasomal degradation. This is mediated by upregulating the ubiquitin-specific proteases USP28 and limiting FBW7-mediated ubiquitination of c-Myc. Moreover, the depletion of PTBP1-caused tumour regression was significantly compromised by exogenous c-Myc expression. Conclusions By preserving the stability of c-Myc through the ubiquitin–proteasome pathway, the oncogene PTBP1 supports stem-cell-like phenotypes of GC and is involved in GC progression.

show abstract

PT109, a novel multi-kinase inhibitor suppresses glioblastoma multiforme through cell reprogramming: Involvement of PTBP1/PKM1/2 pathway

Cited by 9 publications

References 65 publications

Proteomic analysis of holocarboxylase synthetase deficient-MDA-MB-231 breast cancer cells revealed the biochemical changes associated with cell death, impaired growth signaling, and metabolism

Proteomic analysis of holocarboxylase synthetase deficient-MDA-MB-231 breast cancer cells revealed the biochemical changes associated with cell death, impaired growth signaling, and metabolism

Reprogramming Glioblastoma Cells into Non-Cancerous Neuronal Cells as a Novel Anti-Cancer Strategy

PTBP1 drives c-Myc-dependent gastric cancer progression and stemness

Contact Info

Product

Resources

About