Andrographolide sensitizes human renal carcinoma cells to TRAIL‑induced apoptosis through upregulation of death receptor 4

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, with minimal toxicity to normal tissues. However, accumulating evidence suggests that certain cancer types are insensitive to TRAIL signaling. The aim of this study was to identify an effective combination regimen, which can overcome TRAIL resistance in renal cancer cell. Herein, we found that human renal carcinoma cells (RCCs) are widely resistant to TRAIL-mediated growth inhibition and subsequently identified that andrographolide (Andro), a major constituent of Andrographis paniculate, an annual herbaceous plant in the family Acanthaceae, counteracts TRAIL resistance in RCCs. Combined treatment with TRAIL and Andro suppressed cell viability as determined by MTS and proliferation as determined by EdU in a dose-dependent manner and inactivated the clonogenic and migration ability of RCCs. Andro significantly enhances TRAIL-mediated cell cycle arrest at the G2/M phase as determined by flow cytometry and senescence. Moreover, Andro restored TRAIL signaling, which in turns activated pro-apoptosis caspases as determined by immunoblot assay. The TRAIL receptor, death receptor (DR)4, but not DR5, was found to be significantly upregulated in Andro-treated RCC cells, which contributed to the role of Andro as a TRAIL sensitizer. The present study demonstrated that the combined treatment of Andro and TRAIL has potential therapeutic value against renal cancer.

Dysregulation of a lncRNA within the TNFRSF10A locus activates cell death pathways

“…6], our data support the notion that, unlike AC100861.1, upregulated TNFRSF10A leads to apoptosis rather than necroptosis. Other studies have come to similar conclusions, nding increased sensitivity to TRAIL-induced apoptotic signaling in response to upregulated TNFRSF10A (44)(45)(46)(47). On the other hand, we observed that downregulation of TNFRSF10A led to decreased CASP3, CASP8, FADD, and MLKL expression, along with a decrease in phos-MLKL levels [Fig.…”

Transcriptome-Wide High-Throughput m6A Sequencing of Differential m6A Methylation Patterns in the Human Rheumatoid Arthritis Fibroblast-Like Synoviocytes Cell Line MH7A

“… 45 , 46 TNFRSF10A can not only induce apoptosis but also inhibit inflammation, and its ligands can activate the NF-κB pathway and promote cell proliferation and migration. 47 , 48 Li et al 49 found that TNFRSF10A was involved in apoptosis induced by endoplasmic reticulum stress, and TNFRSF10A knockout reduced the expression level of TNFRSF10B, thereby protecting cells from apoptosis. RIPK2 is the downstream target of the pattern recognition receptors NOD1 and NOD2 and is closely related to inflammatory diseases.…”

Andrographolide: A review of its pharmacology, pharmacokinetics, toxicity and clinical trials and pharmaceutical researches

“…Given that the toxicity and side effects has been acknowledged with the vast majority of chemotherapeutic agents, in the past few decades, researchers have paid increasing attention to the anticancer investigation of natural active ingredients, especially andrographolide (Islam et al, 2018; Malik et al, 2021; Soo et al, 2019). Published projects have validated the multiple anticancer effects, such as its ability to colon cancer (Banerjee et al, 2021; Vukmirovic, Vo, Seymour, Rollo, & Mothersill, 2021), lung cancer (Luo et al, 2021), cervical cancer (Pasha et al, 2021), breast cancer (Wanandi et al, 2020), hepatoma cancer (Shi, Zhang, Zheng, Lu, & Ji, 2017) as well as renal carcinoma (Bi et al, 2020) and so on, which the cytotoxic effects on these cancer cells above were bound up with inhibiting proliferation (Khan, Mahfooz, & Ansari, 2020), migration and invasion (Pearngam, Kumkate, Okada, & Janvilisri, 2019), blocking cell cycle (Khan, Mahfooz, Faisal, Alatar, & Ansari, 2020), inducing apoptosis (Wang et al, 2020), restraining tumor angiogenesis (Kajal et al, 2019), as well as enhancing chemosensitivity (Li et al, 2020; Mao, He, Wang, Wu, & Wei, 2019). The main anticancer mechanisms of andrographolide are depicted in Figure 4.…”