Chromosome Region Maintenance 1 (CRM1), also known as Exportin 1 (XPO1), is a protein found in nearly all human cells. CRM1 plays a fundamental role in maintaining normal cellular operations. It functions as a major transporter, facilitating the movement of large molecules like specific proteins and RNA. Its activity is necessary for cellular processes to unfold correctly.
The Role of CRM1 in Cellular Transport
A cell’s nucleus acts as its control center, housing genetic material and regulatory proteins. For these molecules to perform their functions throughout the cell, they must move between the nucleus and the surrounding cytoplasm. CRM1 serves as a dedicated nuclear export protein, transporting specific protein “cargo” from the nucleus to the cytoplasm.
This transport begins when CRM1 binds to its protein passengers, which carry a specific molecular “tag” called a leucine-rich nuclear export signal (NES). A small protein called Ran, when bound to GTP, assists CRM1 in associating with its cargo within the nucleus. The entire complex then navigates through nuclear pore complexes to reach the cytoplasm. Once in the cytoplasm, an enzyme called RanGAP triggers cargo release, allowing CRM1 to return to the nucleus for another round of transport. This tightly controlled movement of molecules is a foundational process for healthy cell function.
CRM1’s Connection to Cancer
Many types of cancer cells exhibit an abnormally high amount of CRM1 protein, a phenomenon referred to as overexpression. This elevated presence of CRM1 promotes cancer growth and survival. The consequence of this overexpression is that CRM1 begins to export particular proteins, known as tumor suppressor proteins, out of the nucleus at an accelerated rate.
These tumor suppressor proteins, such as p53, p21CIP, p27KIP1, FOXO, IκB, and BRCA1, typically reside within the nucleus. There, they act as the cell’s mechanisms to regulate growth, monitor cellular integrity, and initiate programmed cell death if a cell becomes damaged. By removing these protective proteins from the nucleus and relocating them to the cytoplasm, overactive CRM1 disables their ability to control cell division or trigger self-destruction. This mislocalization allows cancer cells to proliferate unchecked and survive when they should naturally be eliminated, directly contributing to tumor progression and potentially leading to resistance to certain therapies. Research indicates that higher CRM1 expression levels are associated with a less favorable patient outlook, increased tumor size, and a greater likelihood of metastasis across various malignancies.
Targeting CRM1 for Treatment
Given CRM1’s role in cancer progression, it has become a promising target for therapeutic intervention. A class of drugs known as Selective Inhibitors of Nuclear Export (SINEs) has been developed to counteract the overexpression of CRM1 in cancer cells. These compounds work by directly binding to and blocking the CRM1 protein, preventing it from transporting its cargo out of the nucleus.
SINEs attach to a specific site within CRM1’s nuclear export signal (NES)-binding groove. This binding action disrupts the formation of the complex between CRM1, RanGTP, and the cargo protein, effectively jamming the nuclear export machinery. As a result, tumor suppressor proteins, which were previously aberrantly exported, become trapped inside the nucleus. Once retained in their proper location, these proteins can resume their normal functions of regulating cell growth and initiating programmed cell death in cancerous cells.
The impact of CRM1 inhibition is more pronounced on cancer cells, often leading to increased apoptosis, while normal cells generally tolerate these compounds. An example of an FDA-approved SINE drug is Selinexor, marketed as XPOVIO. Selinexor is administered orally and has received approval for treating specific types of cancer, including certain forms of relapsed or refractory multiple myeloma and diffuse large B-cell lymphoma. Beyond its direct effects, SINE compounds may also enhance the effectiveness of other anti-cancer drugs by ensuring that tumor suppressors and cell cycle inhibitors remain within the nucleus where they can exert their beneficial effects.