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.
Highlights
Soft tissue sarcomas (STS) are rare solid malignant tumors with different histologies and are commonly characterized by aggressive characteristics locally and in distant metastases [1,2]
We report, for the first time, that 6-Shogaol has strong antigrowth effects on SW872 and 93T449 cells, and its growth-inhibitory and proapoptotic effects on SW872 cells are mediated through regulation of the intrinsic caspase pathway, oxidative stress, Signal transducer and activator of transcription-3 (STAT-3), AMPK, and endoplasmic reticulum (ER) stress
We have demonstrated that 6-Shogaol has anti-survival and pro-apoptotic effects on SW872 human liposarcoma cells, and these effects are mediated through regulation of the intrinsic caspase pathway, oxidative stress, STAT-3, AMPK, and ER stress
Summary
Soft tissue sarcomas (STS) are rare solid malignant tumors with different histologies and are commonly characterized by aggressive characteristics locally and in distant metastases [1,2]. Apoptosis (programmed cell death) has received much attention as a possible mechanism for the elimination of extensively proliferating cancerous cells. Caspase activities are regulated by the family of the B-cell lymphoma-2 (Bcl-2) and inhibitor of apoptosis protein (IAP) [10,11]. A wealth of information illustrates that activation of AMPK contributes to the induction of apoptosis in several cancer cells exposed to anticancer drugs [15,16,17]. STAT-3 is constitutively activated and provides neoplastic cells with proliferation signals with survival advantages, and genetic silencing or pharmacological inhibition of STAT-3 leads to the induction of growth suppression and apoptosis [19,20,21]. We report, for the first time, that 6-Shogaol has strong antigrowth effects on SW872 and 93T449 cells, and its growth-inhibitory and proapoptotic effects on SW872 cells are mediated through regulation of the intrinsic caspase pathway, oxidative stress, STAT-3, AMPK, and ER stress
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