Striatins (STRNs) are generally considered to be cytoplasmic proteins, with lower expression observed in the nucleus and at cell–cell contact regions. Together with protein phosphatase 2A (PP2A), STRNs form the core region of striatin-interacting phosphatase and kinase (STRIPAK) complexes through the coiled-coil region of STRN proteins, which is crucial for substrate recruitment. Over the past two decades, there has been an increasing amount of research into the biological and cellular functions of STRIPAK members. STRNs and the constituent members of the STRIPAK complex have been found to regulate several cellular functions, such as cell cycle control, cell growth, and motility. Dysregulation of these cellular events is associated with cancer development. Importantly, their roles in cancer cells and clinical cancers are becoming recognised, with several STRIPAK components found to have elevated expression in cancerous tissues compared to healthy tissues. These molecules exhibit significant diagnostic and prognostic value across different cancer types and in metastatic progression. The present review comprehensively summarises and discusses the current knowledge of STRNs and core STRIPAK members, in cancer malignancy, from both cellular and clinical perspectives.

(1) Introduction: Claudin-9 (CLDN9) is a member of the claudin protein family, a critical transmembrane protein family for tight junctions that are implemented in the progression of numerous cancer types. The present study investigated the role that CLDN9, along with the subcoat proteins, Zonula Occludens (ZOs), plays in clinical breast cancer and subsequent impact on drug response of patients. (2) Methods: CLDN9 protein and CLDN9 transcript were determined and correlated with clinical and pathological indicators, together with the status of hormonal receptors. The levels of CLDN9 transcript were also assessed against the therapeutic responses of the patients to chemotherapies by using a dataset from the TCGA database. Breast cancer cell models, representing different molecular subtypes of breast cancer, with differential expression of CLDN9 were created and used to assess the biological impact and response to chemotherapeutic drugs. (3) Results: Breast cancer tissues expressed significantly higher levels of the CLDN9, with the high levels being associated with shorter survival. CLDN9 was significantly correlated with its anchorage proteins ZO-1 and ZO-3. Integrated expression of CLDN9, ZO-1 and ZO-3 formed a signature that was significantly linked to overall survival (OS) (p = 0.013) and relapse-free survival (RFS) (p = 0.024) in an independent matter. CLDN9 transcript was significantly higher in patients who were resistant to chemotherapies (p < 0.000001). CLDN9 connection to chemoresistance was particularly prominent in patients of ER-positive (ER(+)), Her-2-negative((Her-2(−)), ER(+)/Her-2(−) and triple-negative breast cancers (TNBCs), but not in patients with HER-2-positive tumors. In Her-2-negative MCF7 and MDA-MB-231 cancer cells, loss of CLDN9 significantly increased sensitivity to several chemotherapeutic drugs including paclitaxel, gemcitabine and methotrexate, which was not seen in Her-2(+) SKBR3 cells. However, suppressing Her-2 using neratinib, a permanent Her-2 inhibitor, sensitized cellular response to these chemodrugs in cells with CLDN9 knockdown. (4) Conclusions: CLDN9 is an important prognostic indicator for patients with breast cancer and also a pivotal factor in assessing patient responses to chemotherapies. Her-2 is a negating factor for the treatment response prediction value by CLDN9 and negating Her-2 and CLDN9 may enhance breast cancer cellular response to chemotherapeutic drugs.

Introduction: Gastric cancer remains a major cause of cancer-related mortality, largely due to invasion, metastasis, and therapeutic resistance. Dysregulated cholesterol metabolism is increasingly recognised as a driver of gastric cancer progression, but how intracellular cholesterol trafficking contributes to malignant junctional remodelling remains poorly understood. MLN64/STARD3 is a cholesterol-binding lipid transfer protein associated with cancer progression, yet its functional role in gastric cancer cell architecture and aggressiveness has not been fully defined. Methods: In this study, we investigated whether MLN64 is associated with cholesterol-dependent tight junction organisation and malignant behaviour in gastric cancer cells. Results: Stable MLN64 knockdown in AGS and HGC-27 cells reduced membrane-associated free cholesterol, as shown by an approximately 50% decrease in the Filipin III membrane/cytoplasm fluorescence ratio in both cell lines. MLN64 depletion was also associated with reduced ZO-1 protein abundance, disrupted junctional ZO-1 localisation, and impaired tight junction integrity, including reduced transepithelial resistance, altered impedance, and increased paracellular permeability. Functionally, MLN64 depletion attenuated gastric cancer cell proliferation and invasive capacity, supporting an association between this cholesterol-trafficking axis, junctional organisation, and aggressive cellular phenotypes. To explore the pharmacological tractability of this pathway, in silico screening of an FDA-approved drug library identified Digoxin and Targretin as candidate compounds predicted to interact with the MLN64 START domain. Digoxin showed a favourable predicted binding energy of -13.73 kcal/mol. Functional validation showed that these agents phenocopied several effects of MLN64 depletion, including altered cholesterol distribution, reduced junctional ZO-1 organisation, impaired adhesion/migration dynamics, and reduced barrier function. Conclusion: Together, these findings identify MLN64 as a regulator associated with cholesterol-dependent tight junction remodelling in gastric cancer cells. Digoxin and Targretin provide preliminary evidence that this pathway may be pharmacologically tractable; however, direct target-engagement and rescue studies will be required to establish causality and determine whether their effects are mediated through direct interaction with MLN64. The MLN64- cholesterol axis may represent a potential vulnerability in gastric cancer membrane organisation and progression.