A novel 3’,5’-diprenylated chalcone induces concurrent apoptosis and GSDME-dependent pyroptosis through activating PKCδ/JNK signal in prostate cancer

Abstract

Although androgen deprivation therapy may initially be effective in prostate cancer, the disease can gradually progress to castration-resistant prostate cancer, at which point chemotherapy becomes the major clinical strategy. In this study, we demonstrated the anti-cancer potential of a novel 3',5'-diprenylated chalcone (C10), which selectively inhibited the proliferation of PC3 cells in vitro and in vivo. C10 treatment elevated the proportion of PC3 cells in sub-G1 phase and induced programmed cell death. Interestingly, C10 elicited concurrent Caspase-dependent apoptotic and gasdermin E-dependent pyroptotic events. RNA-Seq and bioinformatics analyses revealed a strong correlation between protein kinase C delta (PKCδ) and mitogenactivated protein kinase pathway activation in prostate cancer. PKCδ silencing in PC3 cells suppressed the activation of the JNK pathway and the expression of its downstream genes, including Bax, interleukin-6 and interleukin-1β, which are involved in apoptotic and pyroptotic processes. Moreover, in PC3 cell xenograft tumor tissues, C10 treatment inhibited tumor growth and upregulated PKCδ. These findings suggest that C10 treatment induces the PKCδ/JNK pathway, thereby activating Caspase-3 and inducing the cleavage of PARP and gasdermin E to execute apoptosis and cell-lytic pyroptosis in prostate cancer cells.

Induction of Pyroptosis: A Promising Strategy for Cancer Treatment

“…Pyroptosis, apoptosis and necroptosis are three PCD pathways that have been intensively investigated recently. Although induced by distinct mechanisms, the three modes of cell death share many similarities and could be activated alone or simultaneously depending on diverse cellular contexts (26,30,38,39). To better comprehend PCD in cancer treatment, it is necessary to distinguish their main characteristics briefly ( Table 1).…”

“…Zhang et al designed and synthesized a series of novel 3',5'-diprenylated chalcones to develop new chemotherapy drugs. One of these chalcones(C10) was found to induce both apoptosis and GSDME-dependent pyroptosis through activating PKCd/JNK signing pathway (38). In nasopharyngeal carcinoma, Taxol activated caspase-1/GSDMD pathway to induce pyroptosis.…”

“…The use of compounds that are widely available and easy to extract would help reduce the cost of clinical chemotherapy. Besides, the structure of some natural compounds offers prospective possibilities for the synthesis and development of new chemotherapeutic drugs (38). Actively screening and researching chemotherapeutic drugs, natural compounds and artificially synthesized reagents that induce pyroptosis will further improve the existing treatment for malignant tumors.…”

Incaspitolide A extracted fromCarpesium cernuuminduces apoptosisin vitrovia the PI3K/AKT pathway in benign prostatic hyperplasia

“…Its NMR data are as follows: 1 H-NMR (400 MHz, CDCl 3 ) δ: 6.38 (1H, d, J = 1.2 Hz, H-13a), 5.92 (1H, d, J = 1.2 Hz, H-13b), 4.82 (1H, d, J = 11.2 Hz, H-6), 4.63 (1H, dd, J = 1.2, 6.0 Hz, H-9), 4.59 (1H, d, J = 6.0 Hz, H-8), 3.45 (1H, dd, J = 1.6, 11.2 Hz, H-7), 3.03 (1H, m, H-4), 1.12 (3H, s, H-14), 1.01 (3H, d, J = 6.8 Hz, H-15), 13 C NMR (100 MHz, CDCl3) δ: 25.1 (C-1), 33.0 (C-2), 35.4 (C-3), 73.2 (C-4), 77.2 (C-5), 71.0 (C-6), 45.2 (C-7), 78.2 (C-8), 211.1 (C-9), 41.7 (C-10), 132.6 (C-11), 168.4 (C-12), 126.7 (C-13), 20.3 (C-14), 22.0 (C-15), 2 iBu (176.8, 175.1, 33.80, 33.77, 18.9, 18.8, 18.7). It was identified as incaspitolide A by comparison of the physical and spectral data with the literature [ 22 ]. Its purity was 98.65% by HPLC analysis.…”

“…The cytotoxicity of TMJ-12 toward the BPH-1 cell line was measured with the MTT assay according to a previously described protocol [ 22 ]. Briefly, cells were seeded in 96-well plates at a density of 1 × 10 4 cells/well, incubated at 37°C for 24 h, and then treated with TMJ-12 (0, 2, 4, 8, 12, 16 μM) for the indicated time (24 or 48 h).…”