Anti-Survival and Pro-Apoptotic Effects of 6-Shogaol on SW872 Human Liposarcoma Cells via Control of the Intrinsic Caspase Pathway, STAT-3, AMPK, and ER Stress

Abstract

Notably, 6-Shogaol, a bioactive natural substance, has anticancer effects on many types of tumors. Up to date, the anticancer effect and mode of action of 6-Shogaol on liposarcoma are not known. In this study, we investigated whether 6-Shogaol inhibits the growth of SW872 and 93T449 cells, two different human liposarcoma cell lines. Of note, 6-Shogaol inhibited the growth of SW872 and 93T449 cells without affecting that of normal 3T3-L1 preadipocytes. Specifically, 6-Shogaol further induced the apoptosis of SW872 cells, as evidenced by nuclear DNA fragmentation, increased sub G1 population, activation of the intrinsic caspase pathway, and PARP cleavage. However, pretreatment with either z-VAD-fmk, a pan-caspase inhibitor, or N-acetylcysteine, an antioxidant, attenuated the 6-Shogaol’s growth-suppressive and apoptosis-inducing effects on SW872 cells. Moreover, 6-Shogaol activated AMPK while inhibited STAT-3 in SW872 cells, and siRNA-based genetic silencing of AMPK or STAT-3 considerably blocked the growth-suppressive and apoptotic response of 6-Shogaol to SW872 cells. Moreover, 6-Shogaol also upregulated the expression and phosphorylation of GRP-78, eIF-2α, ATF4, and CHOP, known ER stress markers, in SW872 cells, illustrating the induction of ER stress. These findings collectively demonstrate that 6-Shogaol has strong antigrowth and proapoptotic effects on SW872 cells through regulation of the intrinsic caspase pathway, oxidative stress, STAT-3, AMPK, and ER stress.

Growth-Suppressive and Apoptosis-Inducing Effects of Tetrandrine in SW872 Human Malignant Liposarcoma Cells via Activation of Caspase-9, Down-Regulation of XIAP and STAT-3, and ER Stress

“…These findings strongly imply that inhibition and/or knockdown of STAT-3 could be a therapeutic target against cancers in which abnormal STAT-3 activation and expression are problematic. Of interest, it has been recently demonstrated that STAT-3 inhibition induces apoptosis of different types of fibrosarcoma cells [ 42 ]. Of further note, in a recent study, we have demonstrated that STAT-3, but not STAT-5 (another STAT-family members) is substantially expressed and phosphorylated in SW872 cells and its expression and phosphorylation play pivotal roles in the cell survival and apoptosis inhibition based on the facts that STAT-3 gene silencing leads to the cell growth inhibition and apoptosis induction [ 42 ].…”

“…Of interest, it has been recently demonstrated that STAT-3 inhibition induces apoptosis of different types of fibrosarcoma cells [ 42 ]. Of further note, in a recent study, we have demonstrated that STAT-3, but not STAT-5 (another STAT-family members) is substantially expressed and phosphorylated in SW872 cells and its expression and phosphorylation play pivotal roles in the cell survival and apoptosis inhibition based on the facts that STAT-3 gene silencing leads to the cell growth inhibition and apoptosis induction [ 42 ]. In this study, tetrandrine treatment markedly reduces STAT-3 expression and phosphorylation in SW872 cells.…”

Anti-adipogenic and Pro-lipolytic Effects on 3T3-L1 Preadipocytes by CX-4945, an Inhibitor of Casein Kinase 2

“…The cell count analysis was carried out in triplicates. Data are mean ± standard error (SE) of three independent experiments [48].…”

Plant-Derived Compounds as Promising Therapeutics for Vitiligo

“…6-shogaol ( Figure 4I ), a natural phenolic compound, is the major active ingredient in Zingiber officinale Roscoe. Studies have found that 6-shogao possesses antiemetic, anti-inflammatory, antioxidant, and anticancer activities, as well as cardiovascular and neuroprotective effects ( Kou et al, 2018 ; Chen et al, 2020 ; Yadav and Jang 2020 ). Jin et al found that 6-shogaol exerts cellular antioxidant activity by mediating Nrf2 signaling through activation of the JNK pathway ( Kim and Jang 2016 ).…”