Interplay & role reversal of two crucial cellular proteins in regulating spread of cancer cells

17 Jan 2018

Interplay & role reversal of two crucial cellular proteins in regulating spread of cancer cells


By Prof. Annapoorni Rangarajan, Senior Fellow

Indian Institute of Science, Bangalore 

Recent research from our group has demonstrated how two important cellular proteins (and drug targets), Akt and AMPK, undergo a role reversal and interact to regulate the spread of cancer cells, providing a novel therapeutic strategy to control cancer metastasis. 

Majority of cancer-related deaths are due to metastasis, a process by which cancer cells spread from the primary site to distant organs. It involves detachment of the tumor cells from the primary site, entry into the blood or lymphatic system followed by their renewed adhesion at a secondary organ where a new tumor is established. However, cell-detachment from the extracellular matrix triggers cell death known as anoikis. Therefore, detached tumor cells must first learn to survive matrix-deprival and then regain attachment to the substratum at the secondary site in order to induce new tumor growth. It is yet not clear how this reciprocal attachment detachment switch in cancer cells is regulated. Our recently published research shows that two cellular proteins, Akt (Protein Kinase B) and AMPK (5' AMP-activated protein kinase), control this switch by negatively regulating each other.

Akt and AMPK are two important cellular kinases that inversely regulate cellular growth and metabolism. Akt supports building up (anabolic) processes required for growth and proliferation, whereas AMPK promotes breaking down (catabolic) processes that result in growth suppression. However, no link between these two proteins was known thus far in cancer metastasis. Our work reveals that the detachment of breast cancer cells triggers AMPK activity that leads to the concurrent inhibition of Akt. This AMPK-mediated Akt inhibition is necessary for adaptation of cancer cells to survive matrix-deprival. When the detached cancer cells are allowed to re-attach, thus mimicking their establishment at the distant organ, Akt is once again re-activated that leads to the concurrent inactivation of AMPK. We further show that two enzymes named PHLPP and PP2C-α mediate this switch between Akt and AMPK signaling. Thus, we have identified a molecular switchinvolving AMPK and Akt that controls the growth and survival of cancer cells during the attachment ↔ detachment cascade in metastasis.

Our work enriches the cancer field by challenging and contradicting the existing dogma in which Akt is required for cell survival and for promoting tumorigenesis whereas AMPK is thought to have a tumor-suppressive function. In our study, we establish a contextual role-reversal for these two proteins in breast cancer progression.

This study further predicts AMPK inhibition as a novel strategy to curb metastatic cancer spread. Ironically, the anti-diabetic drug metformin, which activates AMPK, is currently being repurposed for cancer treatment. Our findings raise concern on possible pro-metastatic side effects of metformin, suggesting that the potential of AMPK-targeting agents in cancer treatment needs further investigations.

AMPK-AKT double negative feedback loop in breast cancer cells regulates their adaptation to matrix deprivationManipa Saha, Saurav Kumar, Shoiab Bukhari, Sai A Balaji, Prashant Kumar, Sravanth K, Hindupur and Annapoorni Rangarajan*. Cancer Research. January 2018

Banner image credit: Annapoorni Rangarajan Description: Matrix-detached breast cancer cells (MDA MB 231) show active AMPK. Confocal image, Colour: merged phosphorylated AMPK (red); nucleus (green, yellow)