bims-midomi 2026-01-18 papers

FEBS Lett. 2026 Jan 12.

E6-associated protein induces ubiquitin-dependent proteasomal degradation of p53 phosphorylated at Ser-15 in response to genotoxic stress.

Yerin Kwon, Hyunyoung Yoon, Jiwoo Han, Ji-Min Park, Kyung Lib Jang.

The tumor suppressor p53 is normally maintained at low levels through MDM2-mediated degradation; however, this regulation becomes ineffective upon DNA damage, leading to p53 phosphorylation and accumulation. This study shows that E6-associated protein (E6AP) provides an alternative regulatory pathway during genotoxic stress. Unlike MDM2, E6AP can effectively decrease p53 levels in HepG2 cells exposed to DNA-damaging agents, such as etoposide. Additionally, E6AP specifically targets p53 phosphorylated at serine-15, promoting its proteasomal degradation, whereas MDM2 cannot. This phosphorylation-dependent regulation by E6AP helps maintain p53 at appropriate levels during mild DNA damage, preventing excessive accumulation that could threaten cell survival, while still allowing for necessary stress responses. Impact statement The mechanism by which p53 is negatively regulated under genotoxic stress is largely unknown. E6-associated protein (E6AP), unlike MDM2, downregulates p53 levels following exposure to etoposide. E6AP specifically targets p53 phosphorylated at Ser-15. This mechanism prevents excessive accumulation of p53 that could otherwise reach lethal levels.

Keywords: E6‐associated protein; MDM2; etoposide; p53; proteasomal degradation

DOI: https://doi.org/10.1002/1873-3468.70275

Commun Biol. 2026 Jan 16.

Targeting PAK4 promotes Gemcitabine-induced pyroptosis in pancreatic cancer via NLRP1/caspase-3/GSDME axis.

Tianqi Lu, Yongqi Song, Keke Liang, Zhongbo Zhang, Yang Li, Xiaodong Tan, Xiaodong Li, Feng Li.

Pancreatic cancer remains a highly lethal disease, underscoring the continued importance of chemotherapy. The first-line chemotherapeutic agent Gemcitabine (GEM) exerts its effect by inducing tumor cell apoptosis, a process which can subsequently convert to pyroptosis via GSDME expression. Nevertheless, the emergence of drug resistance has prompted extensive research to identify novel therapeutic targets. p21-activated kinase 4 (PAK4) plays important roles in various tumors, including the inhibition of tumor cell apoptosis. Here, we show that PAK4 inhibits pyroptosis in pancreatic cancer through the NAcht leucinerich-repeat protein-1 (NLRP1)/caspase-9/caspase-3/GSDME axis. PAK4 phosphorylates the E3 ubiquitin ligase mouse double minute 2 homolog (Mdm2) to promote the degradation of NLRP1, thereby inhibiting pyroptosis. Furthermore, inhibition of PAK4 kinase activity promotes GEM-induced suppression of pancreatic cancer growth both in vitro and in vivo. Our study suggests that targeting PAK4 to promote GEM-induced pyroptosis may provide a new therapeutic approach for the treatment of pancreatic cancer.

DOI: https://doi.org/10.1038/s42003-026-09538-6

EMBO Mol Med. 2026 Jan 16.

NOTCH1 intracellular domain stabilization by MDM2 plays a major role in NSCLC response to platinum.

Despite major advances in the clinical management of non-small cell lung carcinoma (NSCLC), most patients treated with first-line platinum-based chemotherapy combined with immune checkpoint inhibitors will relapse, which constitutes an unmet medical need. Here, we found that various DNA damage inducers increase the levels of Notch Intracellular Domain (NICD), the active form of NOTCH1. Mechanistically, we revealed that, upon platinum treatment, the expression levels of both MDM2 and NICD were increased and that MDM2 stabilised NICD through ubiquitination. Using NSCLC patient-derived xenografts displaying intrinsic carboplatin resistance, we demonstrated that combining carboplatin with a γ-secretase inhibitor, which hinders NICD generation, significantly improves survival and reduces tumour growth compared with carboplatin monotherapy. Furthermore, in patients with NSCLC who received platinum-based chemotherapy, the level of MDM2 expression in the tumour correlated with poor progression-free survival, which further validates the key role of MDM2 in response to platinum compounds. Our findings present a new therapeutic opportunity for patients with NSCLC, the most common form of lung cancer.

Keywords: MDM2; NSCLC; Notch; Platinum Chemotherapy; Resistance

DOI: https://doi.org/10.1038/s44321-025-00354-9

Cureus. 2025 Dec;17(12): e98997

Atypical Spindle Cell Lipomatous Tumor: A Scoping Review of Current Insights Into Diagnosis, Pathogenesis, and Management.

Noor Chughtai, Jordan Shelestak, Cortland Brown, Jared Nichols.

Atypical spindle cell/pleomorphic lipomatous tumor (ASPLT) is a recently recognized benign adipocytic neoplasm, distinguished by specific histopathological and immunohistochemical features. Although traditionally classified as a tumor of the limbs and limb girdles, emerging evidence suggests a broader anatomic distribution. A systematic review of the literature was conducted using PubMed to identify ASPLT case reports published within the past decade. Cases were included if they had a confirmed ASPLT diagnosis, while reports describing unrelated neoplasms or limited by language barriers were excluded. Thirteen cases met the inclusion criteria. Data on patient demographics, tumor characteristics, immunohistochemical profiles, and diagnostic methodologies were extracted and analyzed. CD34 expression was observed in 90% of cases, while desmin staining was inconsistently reported and lacked clear diagnostic value. Notably, 69% of cases omitted testing for Rb protein loss, a key marker in ASPLT classification. Unexpected MDM2 positivity was identified in 44% of tested cases, with one demonstrating gene amplification, suggesting potential overlap with atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL). Additionally, ASPLT occurred more frequently in axial locations than previously recognized, with eight cases located in the head, neck, and thoraco-lumbar regions. These findings emphasize the need for standardized diagnostic protocols, including routine Rb evaluation and MDM2 analysis, to ensure accurate classification. Future studies should explore the significance of MDM2 expression in ASPLT and reassess its anatomic predilection to refine diagnostic criteria and clinical management strategies.

Keywords: diagnostic pathology; immunohistochemistry; lipomatous neoplasm; soft tissue tumor; spindle cell tumor

DOI: https://doi.org/10.7759/cureus.98997

Int J Surg Case Rep. 2025 Dec;137 112091

One case of left atrial arterial intimal sarcoma.

Zhou Qiao, Zhang Mengsi.

Background: To explore the clinical and pathological characteristics as well as immunophenotypes of arterial endometrial sarcoma, and to improve the understanding of this disease. Due to the poor efficacy of late stage radiotherapy and chemotherapy, early diagnosis and surgical eradication are of great significance.
Method: Clinical data of a case of arterial intimal sarcoma occurring in the left atrium were summarized, HE and immunohistochemical staining were performed to observe its morphological and immunophenotypic characteristics, and relevant literature was reviewed.
Result: The patient was a middle-aged female. Cardiac CT showed a local right bulging of the left atrial septum, while cardiac ultrasound showed an enlargement of the left atrium. Several moderately uneven echogenic tumor reflections were observed in the atrial cavity, with a large amplitude of oscillation. The local echo of the interventricular septum is thin and soft, forming a tumor like structure that swells towards the right atrium. Under the microscope, the tumor cells appear spindle shaped overall, with obvious cellular atypia. Nuclear division and sparse and dense areas of cells can be seen, with some areas showing mucinous stroma and others showing abundant cells growing around blood vessels. Immunohistochemistry confirmed MDM2 positivity.
Conclusion: Endometrial sarcoma is a rare malignant tumor that occurs in the endometrium and may originate from multifunctional stem cells beneath the endometrium. Endometrial sarcoma IS is often a high-grade undifferentiated sarcoma that can differentiate in multiple directions. Combining specific disease sites with morphological diagnosis is not difficult.

Keywords: Angiosarcoma; Case report; Endometrial sarcoma; Soft tissue sarcoma

DOI: https://doi.org/10.1016/j.ijscr.2025.112091