Abstract
The antitumor activity of an inhibitor of 26S proteasome bortezomib (Velcade) has been observed in various malignancies, including colon cancer, prostate cancer, breast cancer, and ovarian cancer. Bortezomib has been proposed to stimulate autophagy, but scientific observations did not always support this. Interactions between ERK activity and autophagy are complex and not completely clear. Autophagy proteins have recently been shown to regulate the functions of ERK, and ERK activation has been found to induce autophagy. On the other hand, sustained activation of ERK has also been shown to inhibit the maturation step of the autophagy process. In this study, we sought to identify the mechanism of autophagy regulation in cancer cells treated with bortezomib. Our results indicate that bortezomib blocked the autophagic flux without inhibiting the fusion of the autophagosome and lysosome. In ovarian cancer, as well as endometrial cancer and hepatocellular carcinoma cells, bortezomib inhibited protein degradation in lysosomes by suppressing cathepsins, which requires the participation of ERK phosphorylation, but not JNK or p38. Our findings that ERK phosphorylation reduced cathepsins further explain how ERK phosphorylation inhibits the autophagic flux. In conclusion, bortezomib may induce ERK phosphorylation to suppress cathepsin B and inhibit the catalytic process of autophagy in ovarian cancer and other solid tumors. The inhibition of cisplatin-induced autophagy by bortezomib can enhance chemotherapy efficacy in ovarian cancer. As we also found that bortezomib blocks the autophagic flux in other cancers, the synergistic cytotoxic effect of bortezomib by abolishing chemotherapy-related autophagy may help us develop strategies of combination therapies for multiple cancers.
Highlights
Bortezomib (Velcade, formerly known as PS-341), an inhibitor of the 26S proteasome, is approved for the treatment of multiple myeloma.[6]
The formation of GFP-light chain 3 (LC3) puncta increased in a time-dependent manner (Figure 1c), indicating that bortezomib initiated the process of autophagy
Bortezomib increased the levels of Light chain 3-II (LC3-II) in TOV112D, OV90, TOV21G and ES2 ovarian cancer cells in a dose-dependent manner (Figure 1d)
Summary
Bortezomib (Velcade, formerly known as PS-341), an inhibitor of the 26S proteasome, is approved for the treatment of multiple myeloma.[6]. In addition to proteasome inhibition, one of the antimyeloma mechanisms of bortezomib is the inhibition of transcription factor nuclear factor-kappa beta (NF-κB).[6] Blocking the NF-κB pathway increased the sensitivity of cancer cells to chemotherapy and enhanced their cellular susceptibility to apoptosis.[6] Recently, bortezomib has been shown to regulate autophagy in breast cancer, melanoma, head and neck cancer, hepatocellular carcinoma, and prostate cancer.[9,12,13,14,15,16,17] bortezomib-related autophagy regulation has not been reported in ovarian cancer yet. Avi become intermediate, double-membraned, autophagic vacuoles (Avi/d). Upon further fusion with lysosome, these vacuoles become double-membraned, degrading autophagic vacuoles (Avd). Activation of autophagy is beneficial to ovarian cancer cells against chemotherapy, and may account for drug resistance.[33]
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