Akt enhances the vulnerability of cancer cells to VCP/p97 inhibition-mediated paraptosis

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Valosin-containing protein (VCP)/p97 is an AAA+ ATPase crucial for proteostasis.
• VCP is a promising target for cancer therapy due to its role in protein homeostasis.

Purpose of the Study:

• To investigate the therapeutic potential of VCP inhibition in breast cancer.
• To elucidate the mechanism of VCP inhibition-induced cell death and identify factors influencing cancer cell susceptibility.

Main Methods:

• Cell viability assays in breast cancer and non-transformed cells.
• Analysis of cell death mechanisms, including paraptosis markers (ER and mitochondrial dilation).
• Investigation of signaling pathways involved in protein synthesis regulation and cell death.

Main Results:

• VCP inhibition selectively eliminated breast cancer cells by inducing paraptosis.
• Oncogenic HRas sensitized non-transformed cells to VCP inhibition.
• Cancer cell susceptibility was linked to sustained protein synthesis and mTORC2/Akt activation.
• The ATF4/DDIT4 axis amplified VCP inhibition-mediated paraptosis.

Conclusions:

• Targeting VCP induces paraptosis, a selective cell death mechanism effective against breast cancer.
• Exploiting VCP inhibition leverages cancer-specific vulnerabilities related to protein synthesis and Akt signaling.
• VCP inhibition offers a promising therapeutic strategy to selectively eliminate cancer cells while preserving normal tissues.