Hsp70 promotes chemoresistance by blocking Bax mitochondrial translocation in ovarian cancer cells

Yang, Xiaokui; Wang, Jiandong; Wang, Yamei; Wang, Shuyu; Zhang, Weiyuan

doi:10.1016/j.canlet.2012.01.030

Cited by 72 publications

(58 citation statements)

References 35 publications

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“…Effects of PDT may be determined by balancing death and survival for cancer therapy resistance mechanisms (17,18). In previous study, HSP70 was found to regulate the apoptosis of chemoresistant cells by inhibiting pro-apoptotic proteins (19,20). We suggest that HSP70 expression is related to other proteins which regulate cell death and resistance in PDT.…”

Section: Introductionmentioning

confidence: 72%

Effects of HSP27 downregulation on PDT resistance through PDT-induced autophagy in head and neck cancer cells

et al. 2016

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Abstract. We previously reported that photodynamic therapy (PDT) induces cell death in head and neck cancer through both autophagy and apoptosis. Regulation of cell death by autophagy and apoptosis is important to enhance the effects of PDT. Autophagy maintains a balance between cell death and PDT resistance. Downregulation of heat shock protein 27 (HSP27) induces PDT resistance in head and neck cancer cells. Furthermore, HSP70 regulates apoptosis during oxidative stress. However, the role of HSPs in PDT-induced cell death through autophagy and apoptosis is unclear. Therefore, in the present study, we investigated the effects of HSP27 and HSP70 on PDT-induced cell death of oral cancer cells through autophagy and apoptosis. Cancer cells were treated with hematoporphyrin at varying doses, followed by irradiation at 635 nm with an energy density of 5 mW/cm 2 . We determined the changes in HSP expression by determining the levels of PARP-1 and LC3II in PDT-resistant cells. Furthermore, we assessed cell death signaling after downregulating HSPs by transfecting specific siRNAs. We observed that PDT decreased HSP27 expression but increased HSP70 expression in the head and neck cancer cells. Treatment of cells with LC3II and PARP-1 inhibitors resulted in upregulation of HSP70 and HSP27 expression, respectively. Downregulation of HSP27 and HSP70 induced cell death and PDT resistance through autophagy and apoptosis. Moreover, downregulation of HSP27 in PDT-resistant cells resulted in enhanced survival. These results indicate that the regulation of HSP27 and HSP70 plays a principal role in increasing the effects of PDT by inducing autophagic and apoptotic cell death.

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Section: Introductionmentioning

confidence: 72%

Effects of HSP27 downregulation on PDT resistance through PDT-induced autophagy in head and neck cancer cells

et al. 2016

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“…The expression and action of heat shock protein 70 (Hsp70) in cancer cells vary among different types of cancers; in breast cancer, bladder cancer, and osteosarcoma, it constitutes a negative prognostic factor, whereas in esophageal cancer and renal cancer, it reportedly acts as a positive prognostic factor (Ciocca et al 2005;Uozaki et al 2000;Goloudina et al 2012). Since Pocaly et al (2007) first reported that Hsp70 expression is involved in imatinib resistance in chronic myeloid leukemia (CML), several other studies have also identified the involvement of Hsp70 expression in resistance to anticancer agents in other forms of cancer (Yang et al 2012;Behnsawy et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Suppression of heat shock protein 70 by siRNA enhances the antitumor effects of cisplatin in cultured human osteosarcoma cells

Mori

Terauchi

Shirai

et al. 2017

Cell Stress and Chaperones

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Although advances in chemotherapy have improved the prognosis for osteosarcoma, some patients do not respond sufficiently to treatment. Heat shock protein 70 (Hsp70) is expressed at high levels in cancer cells and attenuates the therapeutic efficacy of anticancer agents, resulting in a poorer prognosis. This study investigated whether small interfering RNA (siRNA)-mediated inhibition of Hsp70 expression in an osteosarcoma cell line would enhance sensitivity to cisplatin. The expression of Hsp70 with cisplatin treatment was observed by using Western blotting and real-time reverse transcription polymerase chain reaction (RT-PCR). Changes in the IC 50 of cisplatin when Hsp70 was inhibited by siRNA were evaluated. Cisplatin's effectiveness in inducing apoptosis was assessed by assay of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), caspase-3 activity, and mitochondrial membrane potential. Up-regulation of Hsp70 expression was dependent on the concentration of cisplatin. Inhibition of Hsp70 expression significantly reduced the IC 50 of cisplatin. When cisplatin was added to osteosarcoma cells with Hsp70 expression inhibited, a significant increase in apoptosis was demonstrated in TUNEL, caspase-3, and mitochondrial membrane potential assays. Inhibition of Hsp70 expression induced apoptosis in cultured osteosarcoma cells, indicating that Hsp70 inhibition enhanced sensitivity to cisplatin. Inhibition of Hsp70 expression may provide a new adjuvant therapy for osteosarcoma.

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“…This occurs by preventing TNF-related apoptosis-inducing ligand formation of the death-induced signaling complex through inhibition of death receptors 4 and 5, as well as by inhibiting events in mitochondrial-mediated apoptosis (Guo et al, 2005). In the later case, Hsp70i prevents Bax translocation to themitochondria, preventing release of cytochrome c, an apoptosis inducing factor (Yang et al, 2012). Additionally, Hsp70i mediates both caspase dependent and independent apoptotic pathways by binding Apaf-1, blocking recruitment of procaspase-9 to the apoptosome, and by inhibition of JNK, respectively (Beere et al, 2000; Massey et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Identification of an Allosteric Small-Molecule Inhibitor Selective for the Inducible Form of Heat Shock Protein 70

Howe

Bodoor

Carlson

et al. 2014

Chemistry & Biology

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Summary Inducible Hsp70 (Hsp70i) is overexpressed in a wide spectrum of human tumors and its expression correlates with metastasis, poor outcomes, and resistance to chemotherapy in patients. Identification of small molecule inhibitors selective for Hsp70i could provide new therapeutic tools for cancer treatment. In this work, we used fluorescence-linked enzyme chemoproteomic strategy (FLECS) to identify HS-72, an allosteric inhibitor selective for Hsp70i. HS-72 displays the hallmarks of Hsp70 inhibition in cells, promoting substrate protein degradation and growth inhibition. Importantly, HS-72 is selective for Hsp70i over the closely related constitutively active Hsc70. Studies with purified protein show HS-72 acts as an allosteric inhibitor, reducing ATP affinity. In vivo HS-72 is well-tolerated, showing bioavailability and efficacy, inhibiting tumor growth and promoting survival in a HER2+ model of breast cancer. The HS-72 scaffold is amenable to resynthesis and iteration, suggesting an ideal starting point for a new generation of anticancer therapeutics targeting Hsp70i.

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Hsp70 promotes chemoresistance by blocking Bax mitochondrial translocation in ovarian cancer cells

Cited by 72 publications

References 35 publications

Effects of HSP27 downregulation on PDT resistance through PDT-induced autophagy in head and neck cancer cells

Effects of HSP27 downregulation on PDT resistance through PDT-induced autophagy in head and neck cancer cells

Suppression of heat shock protein 70 by siRNA enhances the antitumor effects of cisplatin in cultured human osteosarcoma cells

Identification of an Allosteric Small-Molecule Inhibitor Selective for the Inducible Form of Heat Shock Protein 70

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