What is Endoplasmic Reticulum Stress Response Induced Apoptosis (ERSR)?

The endoplasmic reticulum (ER) is an organelle in cells. Generally speaking, its job is to help make, store, and sort the many proteins cells make. Cells have to maintain proper calcium ion (Ca2+) balances for the ER to work properly. Calcium levels in the ER are regulated by SERCA enzymes. ^(vi.166)

Why is the ER Important?

Within the ER's job description are two tasks that are crucial to healthy cell function: ^(vi.166)

• Correctly fold large proteins, which can be extremely long molecules. Unfolded and/or damaged proteins create stress in a cell.
• As part of a stress response, ER activates protein-folding repair mechanisms to get rid of malformed or damaged proteins. Referred to as the Endoplasmic Reticulum Stress Response (ERSR), it prevents the accumulation of these proteins, which can interfere with how well cells work.

In the presence of too many unfolded proteins and not enough calcium ions, the ER cannot keep up and triggers apoptotic cell death instead. This is referred to as ERSR-induced apoptosis. ^(vi.166)

Chronic ERSR Can Help Some Cancers Survive

Because cancer cells are characterized by unregulated, dysfunctional growth, they can produce higher levels of damaged proteins. These are just as harmful to cancer cells as they are to healthy, normal cells. ^(vi.166)

As a consequence, some cancers (e.g., in glioma brain tumors) actually maintain a low-grade ERSR for a defense mechanism. Chronic ERSR helps handle the constant dysfunction of cancer cells. Unfortunately, it can also help tumors better withstand the damage caused by treatment, making them resistant to cell death. Scientists suggest one way to counteract this resistance is convert chronic ERSR to apoptotic ERSR. ^(vi.166)

Compounds in Turmeric Use ERSR against Cancer Cells

The most well-studied turmeric compound, curcumin, induces apoptosis is some cancer cells by triggering ERSR. For example: ^{(vi.57, 166)}

• Curcumin inhibits levels of the SERCA enzymes that control the calcium pump in the ER, lowering the amount of Ca2+ available for the ER to fold proteins.
• Interestingly, the ER is also where most tissue cells have high levels of the enzyme β-glucuronidase, which can transform curcumin metabolites back into its more potent parent form.
• Level of unfolded proteins increases and induces apoptotic ERSR.

Several other small molecules in turmeric use mechanisms to induce apoptotic ERSR and increase cancer cell death. These include: ^(vi.166)