Cell Biology International最新文献

Diabetic cardiomyopathy (DCM) is a progressive heart disorder associated with diabetes mellitus, leading to structural and functional cardiac abnormalities. The mechanisms responsible include renin-angiotensin-aldosterone (RAAS) activation, inflammation, apoptosis, and metabolic disturbances. Despite well-established epidemiological links, treatments for DCM are elusive. This study evaluated the efficacy of a novel combination of recombinant Klotho (KL) and the angiotensin receptor blocker telmisartan (TEL) in treating DCM, as well as investigating potential mechanisms involved. DCM was induced with a single dose of streptozotocin (55 mg/kg, i.p.), followed by a 4-week induction period. For treatment, rats were assigned to five groups: Normal control (NC), Diabetic control (DC), DC + KL (0.01 mg/kg, S.C.), DC + TEL (10 mg/kg, p.o.), and KL + TEL combination. Plasma biochemistry assessed cardiac damage (LDH, CK-MB) and stress markers (ANP, BNP). Electrocardiogram (ECG) measured heart parameters, including heart rate (HR), QTc, JT interval, RR interval, and T_peak–T_end intervals. Histological analysis (H&E, Masson's trichrome, and Picrosirius red) was performed to assess myocardial structure and fibrosis. Lastly, immunohistochemistry analysis was performed to check the expression of transforming growth factor-β1 (TGF-β1), pSMAD 2/3, matrix metalloproteinase 9 (MMP9), and PRKN. KL and TEL combination treatment significantly reduced cardiac damage markers, reduced ECG abnormalities, including QT_c, improved HR while suppressing pro-fibrotic signaling, enhancing mitophagy, and decreasing fibroblast proliferation. The involvement of pathways involving TGF-β1, pSMAD-2/3, MMP9, and pFOXO3a conferred protection to the heart in experimental in-vivo settings. These findings suggest that the combination of KL and TEL effectively mitigates key pathological features of DCM, highlighting its potential as a targeted treatment strategy.

Cathepsin B (CTSB) is a lysosomal protease that also operates outside the acidic environment of lysosomes. In healthy cells, CTSB plays a crucial role in processes such as apoptosis, autophagy, and the maintenance of cellular homeostasis. However, in cancer, it contributes significantly to disease progression by promoting invasion and metastasis. This study introduces a novel exploration of the relationship between CTSB and its natural inhibitor, Stefin A (STFA), renal cancer cells. For the first time, we demonstrated the precise regulatory influence of CTSB on STFA expression by investigating their expression in noncancerous embryonic renal cells (Hek293T), renal cancer cells (769p), and nonrenal cancer cells (Du145). This study highlights the intricate interplay between CTSB and its inhibitor, offering new insights into the CTSB/STFA balance that occurs in kidney cancer biology. In this study, we simultaneously examined the mRNA and protein expression of CTSB and STFA in various cancer cell lines by employing CTSB gain-of-function, loss-of-function, and biochemical inhibition approaches to understand the contributions of CTSB expression and activity in influencing STFA levels and their reciprocal subcellular localization. We found that cancer cells exhibited impaired regulation of CTSB and STFA gene expression. In particular, our results indicate that exogenous expression of CTSB significantly alters STFA levels, suggesting a feedback mechanism influenced by CTSB's enzymatic activity. Importantly, the relationship between CTSB and STFA is preserved at the protein level, indicating complex regulatory mechanisms mitigating transcriptional misbalances at the translational level. This study provides insight into the interplay between CTSB and STFA in cancer cells and compares it to their behavior in embryonic cells, highlighting how aberrant CTSB expression can influence its inhibitor and advancing our understanding of this balance in tumor progression.

Total flavonoids of Hedyotis diffusa Willd (TFHDW) is an active compound extracted from Hedyotis diffusa Willd (HDW), one of the most well-known herbs possessing antitumor effects. In this study, the potential antitumor effects of TFHDW were investigated in vitro in mouse prostate cancer cells RM1 and human prostate cancer cells LNCaP and in vivo using a xenograft tumor model involving injection of RM1 cells. Upon TFHDW treatment, RM1 and LNCaP cells exhibited augmented protein expression of the protein inhibitor of activated STAT (PIAS4) and diminished activity of signal transducer and activator of transcription 3 (STAT3), along with impaired proliferative, migratory, and invasive capacities. Ectopic STAT3 expression or PIAS4 silencing in RM1 and LNCaP cells partly annulled the inhibition effect of TFHDW treatment on cell malignant phenotypes. Mechanistic studies revealed that TFHDW elevated transcriptional activity of damage-specific DNA-binding protein 2 via PIAS4/STAT3, consequently enhancing ubiquitination and degradation of androgen receptor (AR) protein. By this, TFHDW alleviated the growth of prostate cancer in vitro and in vivo. Altogether, our work uncovers new insights into the link between TFHDW and the PIAS4/STAT3/AR axis in prostate cancer. These findings may provide a novel therapeutic option for targeting the PIAS4/STAT3/AR axis in prostate cancer.

The role of androgens in lung function is contentious, yet their effects on type II alveolar epithelial cells (AECII)-derived lung cancer models remain underexplored. This study reveals that androgens provide survival advantages to A549 cells, a male lung adenocarcinoma AECII cell line, by promoting wound healing and enhancing stress resilience. We demonstrated that testosterone and dihydrotestosterone (DHT) significantly upregulate aquaporin 3 (AQP3) through androgen receptor (AR) accumulation and ERK pathway activation, thereby mitigating cell death under oxidative stress induced by hydrogen peroxide and cyclic cell-stretching. Testosterone facilitated cellular wound healing by promoting actin cytoskeleton remodeling and focal adhesion complex formation, reliant on AR rather than AQP3. Under air-liquid interface culture conditions, testosterone consistently induced AQP3 upregulation, enhanced actin remodeling, and facilitated cellular wound healing responses. Validation of these findings was achieved through gene expression analyses, protein level assessments, cell imaging, and in vitro wound healing assays. The underlying molecular mechanisms of androgen action were elucidated using AQP3- and AR-specific siRNAs and pharmacological inhibitors. These findings underscore the urgent need to investigate the role of sex hormones in lung cancer and other androgen-responsive epithelial models, focusing on their influence on cancer cell survival and motility.

Lung cancer remains a leading cause of cancer-related mortality, underscoring the urgent need for more effective therapeutic strategies, particularly due to the frequent development of drug resistance. Paclitaxel, a widely used chemotherapeutic agent for non-small cell lung cancer (NSCLC), often faces resistance that limits its clinical efficacy. Therefore, identifying molecular markers that modulate paclitaxel responsiveness is critical. The ubiquitin-proteasome system (UPS), which regulates protein homeostasis, plays a role in cancer progression, apoptosis, and drug resistance, with deubiquitinating enzymes (DUBs), serving as key regulators. Recent studies suggest that targeting specific DUBs may enhance drug sensitivity. This study aimed to investigate the expression patterns of DUB genes in response to paclitaxel treatment. Multiplex RT-PCR and RT-qPCR analysis revealed that USP1, USP5, USP28, and USP34 were downregulated, whereas USP10 and USP36 were upregulated in paclitaxel-treated A549 cells. Western blot analysis confirmed changes in protein levels consistent with mRNA expression for all DUBs except USP10 and USP36, which displayed discordant patterns. Furthermore, paclitaxel-induced apoptosis was verified by altered levels of apoptotic and antiapoptotic proteins including PARP, caspase-3, Bax, Bcl-2, Bcl-XL, and p53. The identification of these DUB genes highlights their potential as biomarkers for predicting drug responsiveness and prognosis during paclitaxel treatment, thereby proposing a new direction for improving the therapeutic efficacy of paclitaxel in NSCLC.

The Signaling Lymphocytic Activation Molecule (SLAM) family receptors play essential roles in regulating immune cell activation, differentiation, and communication. SLAMF5, also known as CD84, has drawn increasing attention in cancer immunology due to its involvement in both tumor progression and immune modulation. This review explores the expression patterns, signaling mechanisms, and functional roles of SLAMF5/CD84 within the tumor microenvironment. SLAMF5/CD84 is expressed on multiple immune cell types and contributes to immune evasion by enhancing regulatory B cell function, promoting myeloid-derived suppressor cell expansion, and upregulating immune checkpoint molecules such as PD-L1. Its expression has been implicated in various hematologic malignancies and solid tumors, including chronic lymphocytic leukemia, multiple myeloma, and triple-negative breast cancer. Emerging therapeutic approaches targeting SLAMF5/CD84—such as monoclonal antibodies and CAR T-cell therapies—offer promising strategies to counteract immunosuppression and improve treatment outcomes. By highlighting recent findings and therapeutic developments, this review underscores the significance of SLAMF5/CD84 as both a prognostic biomarker and a novel target in cancer immunotherapy. Understanding SLAMF5/CD84's multifaceted roles in the tumor immune landscape could support the development of more effective and personalized cancer treatment strategies.

Breast cancer (BC) is a frequently diagnosed neoplasm in women and the second major cause of cancer-related deaths. Many BC patients develop metastasis and advanced tumors, increasing morbidity and mortality. There is substantial evidence that tumor relapses in BC patients are driven by a unique population of cells called cancer stem cells (CSCs). Breast CSCs confer stemness to BC and survive through the maintenance of several mechanisms, among which is the involvement of the mTOR signaling pathway. mTOR and its associated AKT signaling play a crucial role in regulating CSCsin various human cancers, including breast cancer. This study investigated the role of targeting mTOR/AKT signaling in the modulation of cell death in 2D and 3D breast cancer models. Torin-2, a dual mTOR inhibitor, effectively suppressed cell proliferation by inducing mitochondrial apoptosis. The inhibition of mTOR led to a decrease in AKT activity and downregulation of key translational machinery components, including 4EBP1, eIF4E, and p70S6K. Torin-2 treatment activated autophagy signaling in both 2D and 3D cell models. The induction of autophagy was evidenced by an increase in the autophagy protein LC3II/I in response to Torin-2 treatment. In addition, Torin-2 treatment of spheroids derived from breast cancer cells suppressed the expression of stem cell marker ALDH. Altogether, the dual inhibition of mTORC1 and mTORC2 by Torin-2 resulted in a more profound antitumor activity. This broader and more potent inhibition of the mTOR pathway contributes to effectiveness in suppressing 2D and 3D breast cancer cell growth and survival.

The second most significant contributor to the global mortality rate resulting from non-communicable diseases is cancer. Cancer cells are recognized for their interactions with adjacent noncancerous cells, such as immune and stromal cells, within the tumor microenvironment, which play a crucial role in influencing tumor progression, metastasis, and resistance. T cell activation is a pivotal process that facilitates the immune system's ability to combat malignancies, characterized by a multi-step signaling cascade leading to T cell proliferation and differentiation. During this activation phase, T cells release a variety of extracellular vesicles, particularly exosomes, which serve as critical regulators of intercellular communication within the tumor microenvironment. These vesicles contain bioactive molecules such as proteins, microRNAs, and immunomodulatory factors that influence tumor growth, immune evasion, and therapeutic responses. CD8⁺T cell-derived exosomes (CD8⁺T-Exos) have been shown to inhibit tumor metastasis by carrying microRNAs that downregulate tumor-promoting genes while also enhancing immune responses by activating CD8⁺T lymphocytes. By elucidating the diverse functions of CD8⁺T-Exos, this review highlights their potential as both biomarkers and therapeutic agents in cancer treatment.