Blocking the oncogenic kinase PAK1 induces "autophagy" in cancer cells and extends the healthy lifespan.

"Ivermection" ,  that was developed by Prof. Satoshi Omura (2015 Nobel laureate) at Kitasato Institute in Tokyo in 1980s, blocks the oncogenic/ageing kinase PAK1 in cancer cells and inhibits their growth (1). Based on this observation of ours, a Chinese group recently found that the PAK1-blocker "Ivermectin" induces the cytostatic "autophagy" in cancer cells, by further down-regulating another oncogenic kinase AKT (2).  Interestingly, this year Prof. Yoshinori Ohsumi at Tokyo Institute of Technology is expected to receive the 2016 Nobel prize in Physiology/Medicine for his pioneer work on "autophagy" based on genetic analysis of yeast mutants. Thus, two Nobel-winning discoveries linked each other through a third discovery (PAK family kinases such as PAK1) by us in 1977 (in amoebae) at NIH and 1994 (in mammals) at Singapore National University.

Phosphorylation of ATG13 blocks the autophagy

Interestingly, rapamycin which is an inhibitor of another oncogenic/ageing kinase TOR, also induces the autophagy in cancer cells, and TOR directly phosphorylates the ATG13, eventually inactivating the autophagic kinase ATG1 (3).  Moreover, expression of a “non-phosphorylatable” mutant of ATG13 in cells alone induces the autophagy without starvation or rapamycin treatment (3). 

Thus, our obvious immediate question is whether PAK1 also phosphorylates ATG13 directly,  or through activating the oncogenic AKT-TOR signaling pathway.


The autophahy contributes to the longevity
Rapamycin as well as a series of herbal PAK1-blockers such as propolis extend the healthy lifespan of small animals such as C. elegans and mice. Thus, starvation, less-eating (calorie-restriction) or exercise, which also induce the autophagy, also promote the longevity by down-reglating the (oncogenic or anti-autophagic/ageing) PAK1-AKT-TOR signaling pathway.


References: 

1. Hashimoto H¹, Messerli SM, Sudo T, Maruta H.
Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines. Drug Discov Ther. 2009 ; 3(6): 243-6.

2. Dou Q¹, Chen HN², Wang K³, Yuan K¹, Lei Y⁴, Li K¹, Lan J³, Chen Y¹, Huang Z¹, Xie N¹, Zhang L¹, Xiang R⁵, Nice EC⁶, Wei Y¹, Huang C⁷
Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer. Cancer Res. 2016 ; 76(15): 4457-69. 

3. Kamada Y¹, Yoshino K, Kondo C, Kawamata T, Oshiro N, Yonezawa K, Ohsumi Y.

Tor directly controls the Atg1 kinase complex to regulate autophagy. Mol Cell Biol. 2010 ; 30(4): 1049-58.