A novel molecular mechanism of apoptosis resistance regulated by S1P-aPKC signaling

• Published in: Proceedings for Annual Meeting of The Japanese Pharmacological Society Vol. 97; p. 2-B-O08-1
• Main Authors: Kajimoto, Taketoshi, Caliman, Alisha D., Tobias, Irene S., Okada, Taro, Pilo, Caila A., Van, An-Angela, McCammon, J. Andrew, Nakamura, Shun-ichi, Newton, Alexandra C.
• Format: Journal Article
• Language: Japanese; English
• Published: Japanese Pharmacological Society 2023
• ISSN: 2435-4953; 2435-4953
• DOI: 10.1254/jpssuppl.97.0_2-B-O08-1

It is well known that cancer cells have an ability of evasion of apoptosis by cellular stress like nutrient starvation. And the balance between apoptosis signal and apoptosis-resistant signal will determine the fate of cells, dead or alive. Here we found new cell signaling system that plays a role in applying brakes to cell death that in case cancer cells avoid apoptosis by cellular stress like starvation using newly developed biosensor and in silico docking simulation technique. The new cell signaling system is that second messenger, sphingosine 1-phosphate (S1P), directly activates a key cell signaling protein, atypical protein kinase C (aPKC). First, we found that inhibition of aPKC induces apoptosis of cancer cells. Next, for making clear the molecular mechanism of the aPKC-induced apoptosis resistance, we generated a genetically encoded FRET reporter (aPKC-selective CKAR (aCKAR)) that allows specific visualization of aPKC activity in living cells. Using aCKAR we found that intracellular S1P induces activation of aPKC in an S1P receptor-independent manner. Biochemical studies revealed that S1P directly binds to the kinase domain of aPKC isozymes, relieving autoinhibitory constraints to activate the enzyme. In silico docking studies were used to identify potential binding sites for aPKC, one of which was validated by biochemical and aCKAR imaging techniques. Now we got new insights about the player of apoptosis resistance with molecular level, and it has potential for development of new molecular-targeted agents to release brakes against cell death.