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Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma.

Salaroglio IC, Campia I, Kopecka J, Gazzano E, Orecchia S, Ghigo D, Riganti C - Oncotarget (2015)

Bottom Line: We compared primary HMM samples with non-transformed mesothelial cells.By reducing the activity of the Ras/ERK1/2/STAT3/IDO axis, zoledronic acid lowered the kyurenine synthesis and the expansion of Treg cells, and increased the proliferation of T-lymphocytes.Thanks to its ability to decrease Ras/ERK1/2 activity, which is responsible for both Pgp-mediated chemoresistance and IDO-mediated immunosuppression, zoledronic acid is an effective chemo-immunosensitizing agent in HMM cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, University of Torino, Italy.

ABSTRACT
The human malignant mesothelioma (HMM) is characterized by a chemoresistant and immunosuppressive phenotype. An effective strategy to restore chemosensitivity and immune reactivity against HMM is lacking. We investigated whether the use of zoledronic acid is an effective chemo-immunosensitizing strategy. We compared primary HMM samples with non-transformed mesothelial cells. HMM cells had higher rate of cholesterol and isoprenoid synthesis, constitutive activation of Ras/extracellular signal-regulated kinase1/2 (ERK1/2)/hypoxia inducible factor-1α (HIF-1α) pathway and up-regulation of the drug efflux transporter P-glycoprotein (Pgp). By decreasing the isoprenoid supply, zoledronic acid down-regulated the Ras/ERK1/2/HIF-1α/Pgp axis and chemosensitized the HMM cells to Pgp substrates. The HMM cells also produced higher amounts of kynurenine, decreased the proliferation of T-lymphocytes and expanded the number of T-regulatory (Treg) cells. Kynurenine synthesis was due to the transcription of the indoleamine 1,2 dioxygenase (IDO) enzyme, consequent to the activation of the signal transducer and activator of transcription-3 (STAT3). By reducing the activity of the Ras/ERK1/2/STAT3/IDO axis, zoledronic acid lowered the kyurenine synthesis and the expansion of Treg cells, and increased the proliferation of T-lymphocytes. Thanks to its ability to decrease Ras/ERK1/2 activity, which is responsible for both Pgp-mediated chemoresistance and IDO-mediated immunosuppression, zoledronic acid is an effective chemo-immunosensitizing agent in HMM cells.

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Zoledronic acid induces chemo-immunosensitization in mesothelioma cells by downregulating the Ras/ERK1/2/HIF-1α/Pgp and Ras/ERK1/2/STAT3/IDO axesHMM cells have the Ras small GTPase (Ras GTP) and the downstream effectors ERK1/2 kinases (pERK1/2) in a constitutively active form. ERK1/2 kinases phosphorylate on serine the transcription factor HIF-1α (pHIF1α), which is primed to translocate in the nucleus and to increase the transcription of the MDR1 gene, which is translated into Pgp, an efflux transporter of chemotherapeutic drugs (D). Moreover, ERK1/2 kinases phosphorylate STAT3 (pSerSTAT3) that activates the transcription of the IDO gene. The increase of kynurenine (K), a product of IDO activity during the catabolism of tryptophan (T), is paralleled by the decreased T-lymphocyte proliferation and by the increased expansion of the immunosuppressive Tregs subpopulation. These events may confer to mesothelioma a chemoresistant and immunosuppressive phenotype. By inhibiting the FPP synthase (FPPS) and then reducing the supply of FPP necessary to activate Ras, zoledronic acid (ZA) inhibits both the Ras/ERK1/2/HIF-1α/Pgp and the Ras/ERK1/2/STAT3/IDO axes, thus potentially inducing chemo-immunosensitization. Green arrow: stimulation; red line: inhibition; blue arrow: transmembrane diffusion or transport.
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Figure 6: Zoledronic acid induces chemo-immunosensitization in mesothelioma cells by downregulating the Ras/ERK1/2/HIF-1α/Pgp and Ras/ERK1/2/STAT3/IDO axesHMM cells have the Ras small GTPase (Ras GTP) and the downstream effectors ERK1/2 kinases (pERK1/2) in a constitutively active form. ERK1/2 kinases phosphorylate on serine the transcription factor HIF-1α (pHIF1α), which is primed to translocate in the nucleus and to increase the transcription of the MDR1 gene, which is translated into Pgp, an efflux transporter of chemotherapeutic drugs (D). Moreover, ERK1/2 kinases phosphorylate STAT3 (pSerSTAT3) that activates the transcription of the IDO gene. The increase of kynurenine (K), a product of IDO activity during the catabolism of tryptophan (T), is paralleled by the decreased T-lymphocyte proliferation and by the increased expansion of the immunosuppressive Tregs subpopulation. These events may confer to mesothelioma a chemoresistant and immunosuppressive phenotype. By inhibiting the FPP synthase (FPPS) and then reducing the supply of FPP necessary to activate Ras, zoledronic acid (ZA) inhibits both the Ras/ERK1/2/HIF-1α/Pgp and the Ras/ERK1/2/STAT3/IDO axes, thus potentially inducing chemo-immunosensitization. Green arrow: stimulation; red line: inhibition; blue arrow: transmembrane diffusion or transport.

Mentions: In summary, we propose that the constitutively active Ras/ERK1/2 axis may determine both the chemoresistance and the immunosuppression observed in HMM. By phosphorylating and activating HIF-1α, this axis promotes the up-regulation of Pgp, which effluxes several chemotherapeutic drugs. By phosphorylating and activating STAT3, it favors the synthesis of kynurenine, which is paralleled by the reduced proliferation of T-lymphocytes and by the increased expansion of the pro-immunosuppressive Tregs population. Thanks to its ability to decrease isoprenoid synthesis and Ras/ERK1/2 activity, zoledronic acid reverses the chemoresistance to Pgp substrates, lowers the kynurenine synthesis and the Tregs proliferation, and restores the proliferation of T-lymphocytes co-cultured with HMM cells (Figure 6).


Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma.

Salaroglio IC, Campia I, Kopecka J, Gazzano E, Orecchia S, Ghigo D, Riganti C - Oncotarget (2015)

Zoledronic acid induces chemo-immunosensitization in mesothelioma cells by downregulating the Ras/ERK1/2/HIF-1α/Pgp and Ras/ERK1/2/STAT3/IDO axesHMM cells have the Ras small GTPase (Ras GTP) and the downstream effectors ERK1/2 kinases (pERK1/2) in a constitutively active form. ERK1/2 kinases phosphorylate on serine the transcription factor HIF-1α (pHIF1α), which is primed to translocate in the nucleus and to increase the transcription of the MDR1 gene, which is translated into Pgp, an efflux transporter of chemotherapeutic drugs (D). Moreover, ERK1/2 kinases phosphorylate STAT3 (pSerSTAT3) that activates the transcription of the IDO gene. The increase of kynurenine (K), a product of IDO activity during the catabolism of tryptophan (T), is paralleled by the decreased T-lymphocyte proliferation and by the increased expansion of the immunosuppressive Tregs subpopulation. These events may confer to mesothelioma a chemoresistant and immunosuppressive phenotype. By inhibiting the FPP synthase (FPPS) and then reducing the supply of FPP necessary to activate Ras, zoledronic acid (ZA) inhibits both the Ras/ERK1/2/HIF-1α/Pgp and the Ras/ERK1/2/STAT3/IDO axes, thus potentially inducing chemo-immunosensitization. Green arrow: stimulation; red line: inhibition; blue arrow: transmembrane diffusion or transport.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 6: Zoledronic acid induces chemo-immunosensitization in mesothelioma cells by downregulating the Ras/ERK1/2/HIF-1α/Pgp and Ras/ERK1/2/STAT3/IDO axesHMM cells have the Ras small GTPase (Ras GTP) and the downstream effectors ERK1/2 kinases (pERK1/2) in a constitutively active form. ERK1/2 kinases phosphorylate on serine the transcription factor HIF-1α (pHIF1α), which is primed to translocate in the nucleus and to increase the transcription of the MDR1 gene, which is translated into Pgp, an efflux transporter of chemotherapeutic drugs (D). Moreover, ERK1/2 kinases phosphorylate STAT3 (pSerSTAT3) that activates the transcription of the IDO gene. The increase of kynurenine (K), a product of IDO activity during the catabolism of tryptophan (T), is paralleled by the decreased T-lymphocyte proliferation and by the increased expansion of the immunosuppressive Tregs subpopulation. These events may confer to mesothelioma a chemoresistant and immunosuppressive phenotype. By inhibiting the FPP synthase (FPPS) and then reducing the supply of FPP necessary to activate Ras, zoledronic acid (ZA) inhibits both the Ras/ERK1/2/HIF-1α/Pgp and the Ras/ERK1/2/STAT3/IDO axes, thus potentially inducing chemo-immunosensitization. Green arrow: stimulation; red line: inhibition; blue arrow: transmembrane diffusion or transport.
Mentions: In summary, we propose that the constitutively active Ras/ERK1/2 axis may determine both the chemoresistance and the immunosuppression observed in HMM. By phosphorylating and activating HIF-1α, this axis promotes the up-regulation of Pgp, which effluxes several chemotherapeutic drugs. By phosphorylating and activating STAT3, it favors the synthesis of kynurenine, which is paralleled by the reduced proliferation of T-lymphocytes and by the increased expansion of the pro-immunosuppressive Tregs population. Thanks to its ability to decrease isoprenoid synthesis and Ras/ERK1/2 activity, zoledronic acid reverses the chemoresistance to Pgp substrates, lowers the kynurenine synthesis and the Tregs proliferation, and restores the proliferation of T-lymphocytes co-cultured with HMM cells (Figure 6).

Bottom Line: We compared primary HMM samples with non-transformed mesothelial cells.By reducing the activity of the Ras/ERK1/2/STAT3/IDO axis, zoledronic acid lowered the kyurenine synthesis and the expansion of Treg cells, and increased the proliferation of T-lymphocytes.Thanks to its ability to decrease Ras/ERK1/2 activity, which is responsible for both Pgp-mediated chemoresistance and IDO-mediated immunosuppression, zoledronic acid is an effective chemo-immunosensitizing agent in HMM cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, University of Torino, Italy.

ABSTRACT
The human malignant mesothelioma (HMM) is characterized by a chemoresistant and immunosuppressive phenotype. An effective strategy to restore chemosensitivity and immune reactivity against HMM is lacking. We investigated whether the use of zoledronic acid is an effective chemo-immunosensitizing strategy. We compared primary HMM samples with non-transformed mesothelial cells. HMM cells had higher rate of cholesterol and isoprenoid synthesis, constitutive activation of Ras/extracellular signal-regulated kinase1/2 (ERK1/2)/hypoxia inducible factor-1α (HIF-1α) pathway and up-regulation of the drug efflux transporter P-glycoprotein (Pgp). By decreasing the isoprenoid supply, zoledronic acid down-regulated the Ras/ERK1/2/HIF-1α/Pgp axis and chemosensitized the HMM cells to Pgp substrates. The HMM cells also produced higher amounts of kynurenine, decreased the proliferation of T-lymphocytes and expanded the number of T-regulatory (Treg) cells. Kynurenine synthesis was due to the transcription of the indoleamine 1,2 dioxygenase (IDO) enzyme, consequent to the activation of the signal transducer and activator of transcription-3 (STAT3). By reducing the activity of the Ras/ERK1/2/STAT3/IDO axis, zoledronic acid lowered the kyurenine synthesis and the expansion of Treg cells, and increased the proliferation of T-lymphocytes. Thanks to its ability to decrease Ras/ERK1/2 activity, which is responsible for both Pgp-mediated chemoresistance and IDO-mediated immunosuppression, zoledronic acid is an effective chemo-immunosensitizing agent in HMM cells.

Show MeSH
Related in: MedlinePlus