Dual role of protein IRE1 in cancer identified

Scientists at the Pennsylvania State University (PSU) have found that the inositol-requiring enzyme 1 (IRE1) has a dual role in cancer. On the one hand, IRE1 helps regulate the endoplasmic reticulum (ER) stress. On the other hand, IRE1 leads to the degradation of molecules that encode the oncogenic protein, ID1. The findings, described in the journal PNAS, advance the understanding of cancer.

"IRE1 has both pro-oncogenic and tumor-inhibiting capabilities," said senior author Dr. Adam Glick. The laboratory of Dr. Glick mainly focuses on molecular mechanisms and signaling pathways implicated in the development and progression of squamous cell carcinoma (SCC), the second most common form of skin cancer.

IRE1 is an enzyme with both kinase and endoribonuclease activity. IRE1 is an ER transmembrane sensor and mediates the unfolded protein response. Previous studies underscore the significance of IRE1 in cellular homeostasis. However, the function of IRE1 in cancer remains unclear.

In this work, scientists found that IRE1 is regulated by a well-studied protein called Ras. Ras normally regulates the expression of genes involved in cell growth, differentiation and survival. Mutations in the gene encoding Ras are associated with many cancer types. Thus, Ras is classified as an oncogene.

Using skin cells from mice, scientists discovered that mutated or oncogenic Ras triggers an accumulation of misfolded proteins in the ER, which in turn activates IRE1. In a word, oncogenic Ras induces ER stress and IRE1 activation.

The ER is an essential cell organelle, whose main functions include protein folding and processing. Multiple stimuli and pathological conditions can lead to accumulation of unfolded/misfolded proteins in the ER and cause ER stress, which can severely damage cellular functions and threaten cell survival. The cell reacts to ER stress by initiating a defensive process, namely the unfolded protein response.

Scientists found that activated IRE1 helps reduce ER stress through degrading mRNAs that encode proteins in the ER. This may facilitate cell survival and promote cancer development. On the other hand, they identified that one of the targets of IRE1 codes for a protein called ID1. The gene encoding ID1 is well known as an oncogene in various tumors. Scientists demonstrated that ID1 degradation by IRE1α actually drives senescence.

Senescence, which means that cells cease to divide, is widely recognized as a potent tumor suppressive mechanism.

Taken together, the data suggest that IRE1 has both cancer-promoting and cancer-inhibiting activities. The discovery of a link between Ras and a dual role of IRE1 will help understand Ras-induced cancer. It is necessary to place more emphasis on the function of IRE1 in future cancer research.
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