Hsp90 inhibitor 17-AAG sensitizes Bcl-2 inhibitor (-)-gossypol by suppressing ERK-mediated protective autophagy and Mcl-1 accumulation in hepatocellular carcinoma cells

Wang, Bin; Chen, Linfeng; Ni, Zhenhong; Dai, Xufang; Qin, Liyan; Wu, Yaran; Li, Xinzhe; Xu, Liang; Lian, Jiqin; He, Fengtian

doi:10.1016/j.yexcr.2014.08.039

Cited by 28 publications

(20 citation statements)

References 37 publications

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“…ERK activation inhibits the processing of caspase-8 and Bid, thereby turning off the mitochondrial amplification loop [26,27]. Previous studies showed that Mcl-1 protein expression is enhanced due to ERK activation [28][29][30]. In our study, we observed that activation of ERK and protein level of MCL-1 decreased in Msi1 knockdown LH86-TR cells whereas increased in Msi1 overexpressing LH86 cells.…”

Section: Discussionsupporting

confidence: 62%

Msi1 confers resistance to TRAIL by activating ERK in liver cancer cells

et al. 2015

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a b s t r a c tTo investigate TRAIL resistance mechanisms in hepatocellular carcinoma (HCC), we isolated a stable TRAIL-resistant sub-population of the HCC cell line LH86, designated LH86-TR. Differential activation of AKT was not responsible for acquisition of TRAIL resistance. Cells with both congenital and acquired resistance to TRAIL exhibited increased Msi1 expression, which conferred TRAIL resistance by activating ERK. Forced expression of Msi1 decreased the sensitivity of HCC cells to TRAIL both in vitro and in vivo. Conversely, shRNA-mediated depletion of Msi1 enhanced TRAIL efficacy. SiRNA-mediated depletion of ERK overcame TRAIL resistance. Hence, we conclude that Msi1 is a mediator of TRAIL resistance in HCC cells.

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Section: Discussionsupporting

confidence: 62%

Msi1 confers resistance to TRAIL by activating ERK in liver cancer cells

et al. 2015

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“…Furthermore, phosphorylation of Mcl‐1 on Ser159 site by GSK3β (which is downstream of and suppressed by AKT) leads to more rapid degradation of Mcl‐1 . Additionally, in our previous study, we found that the HSP90 inhibitor 17‐AAG sensitizes (−)‐G partially through inhibiting ERK‐mediated Mcl‐1 stabilization . In this study, we uncovered that both p‐ERK and p‐JNK (but not p‐AKT) may contribute to the apoptosis resistance to (−)‐G.…”

Section: Discussionmentioning

confidence: 59%

“…More importantly, (−)‐G has been completed the phase IIb clinical trials for PC (eg, NCT00286806, NCT00286793) and a variety of other cancers (eg, NCT00397293). However, our previous studies have revealed that (−)‐G induces limited apoptosis in HCC and PC cells with high level of Bcl‐2 . Therefore, the strategies that can enhance the chemotherapeutic efficacy of (−)‐G in these refractory cancers are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

The PPARγ agonist rosiglitazone sensitizes the BH3 mimetic (−)‐gossypol to induce apoptosis in cancer cells with high level of Bcl‐2

et al. 2018

Molecular Carcinogenesis

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The BH3 mimetic (-)-gossypol (-)-G has shown promising efficacy to kill several kinds of cancer cells or potentiate current chemotherapeutics. But it induces limited apoptosis in cancer cells with high level of Bcl-2. The nuclear receptor PPARγ and its agonist rosiglitazone can suppress various malignancies. More importantly, rosiglitazone is able to enhance the anti-tumor effects of chemotherapy drugs such as carboplatin and tyrosine kinase inhibitors. In this study, we for the first time demonstrated that rosiglitazone could sensitize (-)-G to induce apoptosis in cancer cells with high level of Bcl-2. Furthermore, we found that (-)-G increased the mRNA level and protein stability of Mcl-1, which weakened the pro-apoptotic effect of (-)-G. Rosiglitazone attenuated the (-)-G-induced Mcl-1 stability through decreasing JNK phosphorylation. Additionally, rosiglitazone upregulated dual-specificity phosphatase 16 (DUSP16), leading to a reduction of (-)-G-triggered JNK phosphorylation. Animal experiments showed that rosiglitazone could sensitize (-)-G to repress the growth of cancer cells with high level of Bcl-2 in vivo. Taken together, our results suggest that the PPARγ agonists may enhance the therapeutic effect of BH3 mimetics in cancers with high level of Bcl-2 through regulating the DUSP16/JNK/Mcl-1 singling pathway. This study may provide novel insights into the cancer therapeutics based on the combination of PPARγ agonists and BH3 mimetics.

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“…Additionally, the human hepatocellular carcinoma cancer often overexpresses Mcl-1, probably because of the various apoptosis inducing factors such as hypoxia, pH imbalances, and altered metabolism in which tumors reside, but also because of the benefits of Mcl-1 protein for cytoprotection [20,21].…”

Section: Discussionmentioning

confidence: 99%

Imperatorin acts as a cisplatin sensitizer via downregulating Mcl-1 expression in HCC chemotherapy

Cheng

et al. 2015

Tumor Biol.

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Acquisition of cisplatin resistance is the common and critical limitation for hepatocellular carcinoma (HCC) therapy. Our study was aimed to determine whether there were conditions under which the addition of imperatorin would reverse the resistance of HCC cells to cisplatin-based therapy. In this study, we found that addition of imperatorin significantly enhanced the cytotoxicity of cisplatin to HCC cells. Since the Mcl-1 was overexpressed in HCC cell lines (HepG2, HepG3B, PLC, Huh7) compared with normal liver cell line (L-O2), we found that the Mcl-1 expression was downregulated by imperatorin but not influenced by cisplatin in HCC cells. In addition, our results showed the combination of imperatorin and cisplatin induced apoptosis and ∆Ψm collapse more significantly compared with treatment of imperatorin or cisplatin alone. Furthermore, the imperatorin-induced sensitization for cisplatin-cytotoxicity to HCC cells was abolished by the transfection of Mcl-1 expression plasmid. Finally, we found that the addition of imperatorin significantly reversed the resistance to cisplatin in cisplatin-resistant HCC cells, which was Mcl-1 dependent. In summary, our study revealed that combination with imperatorin could enhance the antitumor activity of cisplatin via targeting Mcl-1 and reverse the resistance to cisplatin in HCC.

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Hsp90 inhibitor 17-AAG sensitizes Bcl-2 inhibitor (-)-gossypol by suppressing ERK-mediated protective autophagy and Mcl-1 accumulation in hepatocellular carcinoma cells

Cited by 28 publications

References 37 publications

Msi1 confers resistance to TRAIL by activating ERK in liver cancer cells

Msi1 confers resistance to TRAIL by activating ERK in liver cancer cells

The PPARγ agonist rosiglitazone sensitizes the BH3 mimetic (−)‐gossypol to induce apoptosis in cancer cells with high level of Bcl‐2

Imperatorin acts as a cisplatin sensitizer via downregulating Mcl-1 expression in HCC chemotherapy

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