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  • This study evaluated the anti tumor influences of

    2024-04-09

    This study evaluated the anti-tumor influences of LA against HepG2 14613 in vivro, and investigated the molecular mechanisms of inducing apoptosis. Overall, our studies suggested that LA is a promising anti-cancer drug and a possible novel therapeutic agent directed toward the mitochondrial-mediated apoptosis pathway for the treatment of HCC.
    Materials and methods
    Results
    Discussion Cancer has become the second most common health problem in developing countries and a prominent cause of death in developed countries. HCC is a common lethal tumor that influences many individuals worldwide, so it is important to find efficacious chemotherapeutics for the advanced-patients that cannot be removed by surgery. Although several therapeutic agents are available to manage HCC, adverse effects and drug resistance limit their efficacy (Au and Frenette, 2015). TCMs are a fertile source of new anti-cancer agents discovery; however, the detailed mechanisms of their action need further investigation. In this study, our date demonstrated that LA significantly inhibited HepG2 cells viability, suggesting that LA is a novel candidate agent for treating HCC. In the present current study, LA was isolated from PSBE and exerted anti-proliferative and apoptosis-inducing effects in HepG2 cells in vitro. Consistent with our prior study (Ma et al., 2016), our current data demonstrate that LA significantly inhibited proliferation and induced apoptosis in HepG2 cells in a dose- and time-dependent manner. Moreover, the anti- proliferative/anti-tumor properties of LA were further corroborated by a significantly reduced Ki-67 proliferation score in LA-treated cells. A proteomic method (2-DE) was used to identify possible LA-targeted proteins. Nine identified proteins were differentially expressed in LA-treated cells compared with that in control cells. Among them, three proteins (prohibitin, 60S acidic ribosomal protein, and ANXA1) were upregulated and six proteins (tropomodulin-3, alpha-1-antitrypsin, HspB1, haptoglobin-related protein, UQCRC1, and Hsp 70.1) were downregulated. Considering its molecular mechanism remains incomprehensible, the proteomics data provide clues to detect potential protein targets and the apoptosis-inducing influences of LA on HepG2 cells. Among these identified proteins, particularly the expression of protein Hsp 70.1, HspB1, prohibitin, UQCRC1, and ANXA1 are some crucial changed-proteins, which were associated with the mitochondrial-mediated apoptosis pathway. Hsp 70 was increasingly expressed in HCC and strongly prevented apoptosis by inhibiting the release of cytochrome c from mitochondria to cytoplasm and activating caspase-9/3-dependent mitochondrial pathway of apoptosis (Zhao et al., 2017). HspB1, also known as hsp27, was a critical marker in numerous cancer cells. HspB1 could indirectly inhibit activation, oligomerization, and translocation of Bax into mitochondria and reduces the release of apoptosis-inducing factor such as cytochrome c; Moreover, HspB1 opposes Bax-mediated mitochondrial apoptosis through accelerating the activation of PI3K-AKT-dependent pathway (Bakthisaran et al., 2015). Prohibitin is a conservative protein mainly located in mitochondria that is related to regulate cell growth, proliferation, migration, cellular signaling, and apoptosis, as well as stabilize mitochondrial proteins (Yang et al., 2016). Prohibitin was primarily believed to be a chaperone with a tumor-suppressing function localized in the mitochondrial inner membrane (Xu et al., 2013); however, more and more evidence showed that PHB was also located in nuclear matrix and executed its biological function through being moved from the nucleus to the mitochondria (Ritterson and Tolan, 2012). Overexpression of PHB in nucleus may reveal the failed movement to mitochondria and lead the dysfunction of mitochondria. UQCRC1 is an important subunit of complex III in the mitochondrial respiratory chain that catalyzes electron transfer from coenzyme QH2 to ferricytochrome c, leading to an electron gradient (ΔΨm) (Weng et al., 2014, Weng et al., 2014). Upregulation of UQCRC1 may lead to the speedy growth of cancer cells by increasing ATP synthesis. Hence, there are several drugs that inhibit activation of the mitochondrial respiratory chain at complex III to display anti-cancer function (Li et al., 2013). ANXA1 is also mainly involved in controlling cell differentiation, proliferation, and apoptosis, and as a pro-apoptotic protein that regulates tumor cell apoptosis by regulating Bcl-2/Bcl-XL-2-related apoptosis promoter activity and translocation to the mitochondria (Vago et al., 2012). ANXA1 positively regulates the mitochondrial-mediated apoptosis pathway, which relies on release of intracellular pro-apoptotic proteins to active caspases cascade upon DNA damage. Consequently, these proteins mainly are involved in dysfunction of mitochondrial function and induction of cell apoptosis, LA-induced cell apoptosis and mitochondria related function were further evaluated.