Alpha-Lipoic Acid Modulates Melanoma Survival Networks via ER Stress Induction, Mitochondrial Apoptosis, and Kinase Pathway Suppression in B16F10 Cells

Zeylenone-mediated inhibition of TIMP-1-induced Bax/Bcl-2/Cle-caspase-3 expression and apoptosis via FAK-PI3K/AKT pathway regulation in thyroid cancer cells: in vitro and in silico study

Abstract A002: Bcl-2–Dependent Apoptotic Resistance Overcome by (2-Methylbutyryl) Shikonin Through ROS-Driven Mitochondrial Signaling in Melanoma

Skin cancer is one of the most common forms of cancer worldwide, among which melanoma represents the most aggressive and lethal subtype due to its high metastatic potential and resistance to apoptosis. A critical factor underlying melanoma progression and survival is the dysregulation of apoptotic pathways, particularly the overexpression of the anti-apoptotic protein Bcl-2, which enables tumor cells to evade programmed cell death. Therefore, targeting Bcl-2–mediated survival signaling represents a promising therapeutic approach in melanoma treatment. (2-Methylbutyryl) Shikonin (BSHK), a naturally occurring naphthoquinone derivative, has emerged as a potential anti-cancer agent due to its ability to inhibit cancer cell proliferation and induce apoptosis. The present study aimed to investigate the anti-melanoma potential of BSHK with a specific focus on its modulation of Bcl-2–dependent apoptotic pathways. Biological effects were evaluated using MTT assay, Annexin-V/FITC staining, and immunoblotting analysis. The findings revealed that BSHK significantly inhibited melanoma cell growth and viability while inducing a marked increase in intracellular ROS levels. Importantly, BSHK treatment triggered apoptosis in melanoma cells, as evidenced by enhanced Annexin-V positivity. At the molecular level, BSHK markedly downregulated the expression of Bcl-2, while upregulating pro-apoptotic proteins such as BAX and cleaved Caspase-3, thereby shifting the balance toward apoptosis. In conclusion, (2-Methylbutyryl) Shikonin exerts potent anti-melanoma effects primarily through the suppression of Bcl-2–mediated survival pathways and activation of intrinsic apoptotic signaling. These findings highlight BSHK as a promising candidate for targeting apoptosis resistance in melanoma. AALIM MAQSOOD. BHAT, Sheikh Tasduq. Abdullah. Bcl-2–Dependent Apoptotic Resistance Overcome by (2-Methylbutyryl) Shikonin Through ROS-Driven Mitochondrial Signaling in Melanoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr A002.

Quercetin induces molecular hallmarks of immunogenic cell death and cGAS-STING pathway activation via mitochondrial DNA release in hepatocellular carcinoma cells.

It is suggested that QUR concurrently elicits molecular hallmarks of ICD and activates the cGAS‑STING pathway through mtDNA release in HCC cells, which provides a preliminary mechanistic basis for exploring QUR as an immunomodulatory agent for HCC.

Pyrogallol inhibits T cell lymphoma growth by mediating G2/M phase cell cycle arrest, apoptosis, glycolysis and immune evasion: an implication of AKT pathway

Berberine induces PD-L1 degradation via the autophagy-lysosome pathway through the PI3K-Akt pathway and enhances immunogenic cell death in triple-negative breast cancer

Objective This study aimed to investigate the regulatory effect and molecular mechanism of Berberine (BBR) on programmed death-ligand 1 (PD-L1) expression in Triple-Negative Breast Cancer (TNBC) cells. Methods In vitro cellular experiments (using MDA-MB-231 and BT-549 cell lines) and mouse models (Balb/c-nu and Balb/c mice) were performed. Combined with techniques including Western blot and immunofluorescence assay, the effect of BBR on PD-L1 expression was evaluated. Results BBR reduced PD-L1 protein expression in TNBC cells in a time- and dose-dependent manner, decreased the membrane localization of PD-L1, and inhibited interferon-γ (IFN-γ)-induced PD-L1 upregulation. Mechanistically, BBR activated autophagy by inhibiting the PI3K-Akt pathway, leading to PD-L1 degradation primarily mediated by the autophagy-lysosome pathway, with minimal contribution from the proteasome under the conditions tested. Cycloheximide (CHX) pulse-chase assay confirmed the degradation kinetics of PD-L1. Experiments evaluating lysosomal function excluded the influence of abnormal lysosomal function, demonstrating that this degradation was independent of the ubiquitin-proteasome system and did not affect lysosomal function. Furthermore, BBR increased the expression and release of immunogenic cell death (ICD)-associated markers in TNBC cells, including calreticulin (CRT) exposure and high-mobility group box 1 (HMGB1) release. In vivo experiments showed that BBR treatment did not significantly reduce tumor volume or weight in Balb/c-nu mice, but effectively decreased tumor volume and weight in the 4T1 Balb/c mouse model without obvious systemic toxicity. In the tumor tissues of 4T1 Balb/c mice, the proportion of CD8+CD3+ and CD69+CD8+ activated T cells was significantly increased, the expression level of granzyme B in CD8+ T cells was notably elevated, and the number of regulatory T cells (Tregs, CD4+CD25+Foxp3+) was significantly reduced. Conclusion BBR can regulate PD-L1 degradation and induce ICD through the PI3K-Akt-autophagy pathway. Its mode of immune checkpoint degradation and immunogenic activation provides experimental evidence for the immunotherapy of TNBC.

Salvianolic acid B suppresses non-small cell lung cancer growth by promoting Nrf2 proteasomal degradation and triggering autophagy-dependent ferroptosis.