The catalytic subunit p110δ of phosphoinositide 3‐kinase (PI3K) encoded by PIK3CD has been implicated in some human solid tumors. However, its roles in colorectal cancer (CRC) remain largely unknown. Here we found that PIK3CD was overexpressed in colon cancer tissues and CRC cell lines and was an independent predictor for overall survival (OS) of patients with colon cancer. The ectopic overexpression of PIK3CD significantly promoted CRC cell growth, migration and invasion in vitro and tumor growth in vivo. In contrast, inhibition of PIK3CD by specific small‐interfering RNA (siRNA) or Idelalisib dramatically suppressed CRC cell growth, migration and invasion in vitro and tumor growth in vivo. Moreover, PIK3CD overexpression increased AKT activity, nuclear translocation of β‐catenin and T‐cell factor/lymphoid enhancer factor ( TCF / LEF ) transcriptional activity and decreased glycogen synthase kinase 3β (GSK‐3β) activity, whereas PIK3CD inhibition exhibited the opposite effects. Furthermore, PIK3CD mediated cell growth, migration and invasion was reversed by blockade of AKT signaling or depletion of β‐catenin. In addition, PIK3CD expression in colon cancer tissues positively correlated with β‐catenin abnormal expression, which was an independent predictor for OS of colon cancer patients. Taken together, our findings demonstrate that PIK3CD is an independent prognostic factor in CRC and that PIK3CD induces CRC cell growth, migration and invasion by activating AKT/GSK‐3β/β‐catenin signaling, suggesting that PIK3CD might be a novel prognostic biomarker and a potential therapeutic target for CRC.

Inhibitors of cyclin-dependent kinases (Cdks) have been reported to have activities in many types of cancer cells by inhibiting Cdk7 and Cdk9, which control transcription. SNS-032 is a potent and selective inhibitor of Cdk2, Cdk7 and Cdk9 and has emerged in clinical trials. Here, we examined the viability of MCF-7 and MDA-MB-435 breast cancer cells in the presence of SNS-032 and observed a dose-dependent inhibition of cellular proliferation in both cell lines. SNS-032 had a direct apoptosis-inducing effect through both the extrinsic and intrinsic apoptotic pathways in breast cancer cells as shown by a dose-dependent increase in Annexin V-positive cells and terminal deoxynucleotidyl transferase-mediated dUTP nick?end labeling (TUNEL)-positive cells, as well as activation of caspase-8, -9 and poly(ADP-ribose) polymerase (PARP). At the molecular level, SNS-032 induced a marked dephosphorylation of serine 2 and 5 of RNA polymerase (RNA Pol) II and blocked RNA synthesis. Consistent with the inherently rapid turnover rates of their transcripts and proteins, the anti-apoptotic proteins Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP) were rapidly reduced on exposure to SNS-032. Our results also indicated that SNS-032 suppressed the growth of breast cancer xenografts in mice. These data demonstrate that the use of SNS-032 may be a rational and novel therapeutic strategy for human breast cancer and warrants further clinical investigation.

Cuproptosis is a copper-dependent form of regulated cell death that begins when ferredoxin 1 (FDX1) reduces Cu²⁺ to Cu¹⁺, allowing the ion to bind lipoylated enzymes of the tricarboxylic-acid (TCA) cycle, drive protein aggregation, dismantle iron–sulphur clusters and trigger fatal proteotoxic stress. Most tumours, despite accumulating copper, evade this fate through glucose-metabolic rewiring. First, oncogenic stabilisation of hypoxia-inducible factor-1 alpha (HIF-1α) and MYC increases pyruvate dehydrogenase kinase (PDK) activity, which phosphorylates and inactivates the pyruvate dehydrogenase complex (PDC), shrinking the lipoylated target pool in mitochondria and cutting the feed into the TCA cycle. Second, glycolytic signalling suppresses cuproptosis-promoting genes such as FDX1 and dihydrolipoamide S-acetyltransferase while inducing the negative regulator glutaminase (GLS), further lowering copper sensitivity. Third, diversion of glycolytic intermediates into the pentose-phosphate pathway (PPP) supplies abundant nicotinamide adenine dinucleotide phosphate (NADPH), whereas enhanced glutamine catabolism furnishes glutamate; together these fuels expand reduced glutathione (GSH) and metallothionein (MT) pools that chelate Cu¹⁺ and quench reactive oxygen species exactly where cuproptosis is executed. Consequently, glycolysis-dependent cancer cells are far less sensitive to copper-ionophore drugs such as elesclomol or disulfiram than respiration-dependent counterparts, and clinical datasets consistently link high PDK and low PDC-subunit expression with poor prognosis. These insights highlight rational combination strategies: re-activating the TCA cycle with PDK inhibitors, draining PPP- or GLS-driven NADPH/GSH supply, and concurrently delivering copper ionophores could reopen the cuproptotic trap in tumours. Validating such approaches in vivo, charting upstream regulators of FDX1 and mapping crosstalk between cuproptosis and other lethal programmes remain key steps toward exploiting this copper-centred vulnerability in cancer therapy.