Tanshinone IIA induces TRAIL sensitization of human lung cancer cells through selective ER stress induction

Abstract

Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promised anticancer medicine targeting only the tumor, most cancers show resistance to TRAIL-induced apoptosis. For this reason, new therapeutic strategies to overcome the TRAIL resistance are required for more effective tumor treatment. In the present study, potential of tanshinone IIA as a TRAIL sensitizer was evaluated in human non-small cell lung cancer (NSCLC) cells. NSCLC cells showed resistance to TRAIL-mediated cell death, but combination treatment of Tanshinone IIA and TRAIL synergistically decreased cell viability and increased apoptosis in TRAIL-resistant NSCLC cells. Tanshinone IIA greatly induced death receptor 5 (DR5), but not death receptor 4 (DR4). Furthermore, DR5 knockdown attenuated the combination treatment of tanshinone IIA with TRAIL-mediated cell death in human NSCLC cells. Tanshinone IIA also increased CHOP and activated the PERK-ATF4 pathway suggesting that tanshinone IIA increased DR5 and CHOP by activating the PERK-ATF4 pathway. Tanshinone IIA also downregulated phosphorylation of STAT3 and expression of survivin. Taken together, these results indicate that tanshinone IIA increases TRAIL-induced cell death via upregulating DR5 and downregulating survivin mediated by, respectively, selective activation of PERK/ATF4 and inhibition of STAT3, suggesting combinatorial intervention of tanshinone IIA and TRAIL as a new therapeutic strategy for human NSCLC.

Tanshinone IIA suppresses gastric cancer cell proliferation and migration by downregulation of FOXM1

“…Subsequent research further confirmed the anticancer effect of TNS on esophageal, prostate, colorectal, lung and GC (5–8). However, the mechanism by which TSN suppresses GC progression remains unclear.…”

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…Tanshinone IIA is the primary bioactive constituent of tanshinones [502], which has various pharmacological effects, including anti-inflammatory, anti-cancer and anti-atherosclerotic activities, and cardiovascular protection [503][504][505][506]. Tanshinone exhibits anti-cancer activities in stomach, prostate, lung, breast, and colon cancers, through inducing cell cycle arrest, apoptosis, autophagy, and inhibiting cell migration [507][508][509][510][511][512][513][514][515].…”

Chinese Herbal Extractions for Relieving Radiation Induced Lung Injury: A Systematic Review and Meta‐Analysis

“…Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong , Radix Curcumae, and Rhizoma Curcumae promote blood circulation to remove blood stasis. Their extractions tanshinone, LI, and EI relieved RILI in vivo [38] and have antitumor effects against lung cancer [54–56]. EI also enhances the radiosensitivity of lung adenocarcinoma [57].…”