PI3K/Akt Pathway Activation Attenuates the Cytotoxic Effect of Methyl Jasmonate Toward Sarcoma Cells

Abstract

Methyl jasmonate (MJ) acts both in vitro and in vivo against various cancer cell lines. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway results in decreased susceptibility to cytotoxic agents in many types of cancer cells. We found a strong inverse correlation between the basal level of phospho-Akt (pAkt) and the sensitivity to MJ among sarcoma cell lines. Nevertheless, levels of pAkt increased in two sarcoma cell lines, MCA-105 and SaOS-2, after MJ treatment. Treatment of both cell lines with PI3K/Akt pathway inhibitors in combination with MJ resulted in a synergistic cytotoxic effect. Moreover, cells transfected with a constitutively active Akt were less susceptible to MJ-induced cytotoxicity in comparison with cells transfected with an inactive form of Akt. Taken together, these data suggest that the increase in pAkt after treatment with MJ played a protective role. Because it has been shown that the antiapoptotic effects of Akt are dependent on glycolysis, we examined the role of glucose metabolism in activation of Akt and the subsequent resistance of the cell lines to MJ. 2-Deoxy-d-glucose, a glycolysis inhibitor, decreased the levels of pAkt and was able to attenuate the MJ-induced elevation in pAkt. Accordingly, the presence of glucose attenuated MJ-induced cytotoxicity. Moreover, treatment with 2-deoxy-d-glucose in combination with MJ resulted in a synergistic cytotoxic effect. In conclusion, the PI3K/Akt pathway plays a critical role in the resistance of MCA-105 and SaOS-2 sarcoma cell lines toward MJ-induced cytotoxicity.

Strigolactone analogues induce apoptosis through activation of p38 and the stress response pathway in cancer cell lines and in conditionally reprogrammed primary prostate cancer cells.

“…We also noted the transient inhibition of ERK1/2 and a more durable inhibition of AKT in response to SLs. Inhibition of the PI3-K/AKT pathway has been shown to play an important role in the cytotoxic effects of another plant hormone, Methyl Jasmonate [39]. …”

Small interfering RNA library screen of human kinases and phosphatases identifies polo-like kinase 1 as a promising new target for the treatment of pediatric rhabdomyosarcomas

“…In particular, PDK-1/AKT, IGF-2/AKT or ERK, PI3K/AKT, mTOR/Hif-1α/VEGF and STAT3 pathways have been implicated in RMS (19, 24–25, 31–35). Consistent with this, we show by IPA analysis that a majority of the active kinases are associated directly or indirectly with MAP/PI3K/Jnk pathways, and that these pathways lead to the downstream activation of PLK1 that is one of the most important “survival kinases” for RMS identified in the screen.…”

Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

“…Since both Src and Akt are known interaction partners of AR and both phosphorylate AR [ 129 ], these data suggest that the Src-Akt pathway is involved in both SAL- and the antagonist AA-mediated cellular senescence in PCa cells ( Figure 1 and Figure 2 ). Interestingly, in different sarcoma cell lines, the treatment with Akti disrupts the translocation of Akt to the plasma membrane [ 130 ]. Thereby, the activation by membrane-bound phosphatidylinositol-dependent kinases is inhibited [ 131 ].…”