PPP2CA (Protein Phosphatase 2 Catalytic Subunit Alpha 2)

Exploiting this 'death switch' offers a novel therapeutic framework through three principal strategies: (1) inducing pyroptosis to eliminate apoptosis-resistant cells, (2) utilizing pyroptosis-induced inflammation to enhance immune checkpoint inhibitor efficacy, and (3) developing targeted therapeutics that directly modulate these switch molecules. Although controlling pyroptosis-associated inflammation remains challenging, understanding and manipulating the apoptosis-to-pyroptosis transition provides an innovative approach to overcome drug resistance and develop more effective cancer treatments.

Overall, these findings identify RCN2 as a novel driver of ESCC metastasis and CDDP resistance. RCN2 could be a promising treatment target for ESCC.

Targeting the UPS represents a promising strategy to reverse immunosuppression and overcome therapy resistance in CRC. The primary advantage of this approach lies in its ability to simultaneously disrupt multiple immunosuppressive pathways within the TME, offering a potential solution to the limitations of single-target therapies. Current approaches include proteasome inhibitors, E3 ligase modulators, and deubiquitinating enzyme inhibitors, with combination regimens-such as UPS inhibitors with immune checkpoint blockade-showing synergistic efficacy in preclinical models. Future efforts should focus on enhancing the selectivity of UPS-targeting agents, minimizing off-target effects, and integrating genomic profiling to guide personalized treatment. While current evidence strongly supports the therapeutic potential of UPS targeting, its establishment as a reliable alternative therapy in the clinic will depend on overcoming these challenges and validating efficacy in human trials. This review underscores the UPS as a central regulator of the CRC TME and provides a rational basis for novel therapeutic development.

Validation in model cells showed that the expression levels of transferrin receptor (TFRC) and acyl-CoA synthetase long-chain family member 4 (ACSL4) were significantly upregulated. STRING analysis and in-model-cell validation indicated that increased mTOR phosphorylation subsequent to PPP2CA knockdown could upregulate the protein expression levels of transferrin receptor (TfR, encoded by the TFRC gene) and ACSL4, and this effect could be reversed by the mTOR inhibitor rapamycin.​ Thus, PPP2CA knockdown enhances the malignant phenotype of CRC cells, while potentially upregulating the expression of ferroptosis-related genes TFRC and ACSL4 via the mTOR signaling pathway, thereby increasing ferroptosis sensitivity.

These findings support a model in which methionine limitation lowers SAM availability, thereby decreasing PP2A methylation and impairing cell proliferation. Our study reveals a mechanistic link between methionine metabolism and cell proliferation and suggests that PP2A methylation plays a key role in the unique methionine dependence of cancer cells.

Consequently, MKRN2-mediated PPP2CA repression increased β-catenin phosphorylation and decreased its protein levels, causing the inactivation of Wnt signaling pathway and amplification of apoptosis in ccRCC cells. This study demonstrated that the E3 ligase activity of MKRN2 had a pivotal role in regulating the PPP2CA-β-catenin-Wnt pathway and granted MKRN2 as a candidate tumor suppressor in ccRCC.

Overall, this study provides insights on mechanisms for white matter abnormalities caused by loss of PP2A function. The findings in this study may be implicated in the pathogenesis of diseases with defective motor coordination.

The results showed that AuNP-p-CPS62 and AuNP-CPS62, especially the former, effectively suppressed the growth of BRAFV600E/pTERT double mutated cancer cells both in vitro and vivo, with good biosafety. These findings suggest that blocking the interaction between TERT and c-Myc may be a promising therapeutic option for BRAFV600E/pTERT double mutated tumors.

In conclusion, our findings highlight a novel mechanism of action for forskolin and support a potential role of this natural compound in combination with current conventional agent daunorubicin in the treatment of KMT2A-r AML.

Notably, STING activation may induce the compensatory upregulation of immune suppressive factors such as interleukin-35 (IL-35)/programmed cell death 1 ligand 1 (PD-L1), and stratified treatment strategies based on tumor heterogeneity characteristics will become the key to overcoming drug resistance. This article not only constructs a theoretical framework of "immune initiation-microenvironment remodeling-malignant transformation inhibition" in a trinity, but also marks the paradigm shift of tumor immunotherapy from single-pathway activation to multi-scale dynamic regulation, providing a route map that is both innovative and feasible for clinical translation.

Our study reveals that Triptolide effectively inhibits OC progression by targeting the PPP2CA-ITGA5 axis, mitigating lactate-driven metabolic reprogramming.

The main aim is to explain why and how the different Houge-Janssens syndrome subtypes biochemically and clinically overlap, providing a framework for understanding new variants and new subtypes that will be found in the future. Hypothetically, small molecules that alleviate substrate blockade by affected B subunits or correct misfolding of affected A subunit, could represent treatment options, but these remain to be found.