Dramatic suppression of colorectal cancer cell growth by the dual mTORC1 and mTORC2 inhibitor AZD-2014

Colorectal cancer is a major contributor of cancer-related mortality. The mammalian target or rapamycin (mTOR) signaling is frequently hyper-activated in colorectal cancers, promoting cancer progression and chemo-resistance. In the current study, we investigated the anti-colorectal cancer effect of a novel mTOR complex 1 (mTORC1) and mTORC2 dual inhibitor: AZD-2014. In cultured colorectal cancer cell lines, AZD-2014 significantly inhibited cancer cell growth without inducing significant cell apoptosis. AZD-2014 blocked activation of both mTORC1 (S6K and S6 phosphorylation) and mTORC2 (Akt Ser 473 phosphorylation), and activated autophagy in colorectal cancer cells. Meanwhile, autophagy inhibition by 3-methyaldenine (3-MA) and hydroxychloroquine, as well as by siRNA knocking down of Beclin-1 or ATG-7, inhibited AZD-2014-induced cytotoxicity, while the apoptosis inhibitor had no rescue effect. In vivo, AZD-2014 oral administration significantly inhibited the growth of HT-29 cell xenograft in SCID mice, and the mice survival was dramatically improved. At the same time, in xenografted tumors administrated with AZD-2014, the activation of mTORC1 and mTORC2 were largely inhibited, and autophagic markers were significantly increased. Thus, AZD-2014 inhibits colorectal cancer cell growth both in vivo and in vitro. Our results suggest that AZD-2014 may be further investigated for colorectal cancer therapy in clinical trials.     

Ocean acidification and temperature increase impact mussel shell shape and thickness: problematic for protection?

Ocean acidification threatens organisms that produce calcium carbonate shells by potentially generating an under‐saturated carbonate environment. Resultant reduced calcification and growth, and subsequent dissolution of exoskeletons, would raise concerns over the ability of the shell to provide protection for the marine organism under ocean acidification and increased temperatures. We examined the impact of combined ocean acidification and temperature increase on shell formation of the economically important edible mussel Mytilus edulis. Shell growth and thickness along with a shell thickness index and shape analysis were determined. The ability of M. edulis to produce a functional protective shell after 9 months of experimental culture under ocean acidification and increasing temperatures (380, 550, 750, 1000 μatm pCO ₂, and 750, 1000 μatm pCO ₂ + 2°C) was assessed. Mussel shells grown under ocean acidification conditions displayed significant reductions in shell aragonite thickness, shell thickness index, and changes to shell shape (750, 1000 μatm pCO ₂) compared to those shells grown under ambient conditions (380 μatm pCO ₂). Ocean acidification resulted in rounder, flatter mussel shells with thinner aragonite layers likely to be more vulnerable to fracture under changing environments and predation. The changes in shape presented here could present a compensatory mechanism to enhance protection against predators and changing environments under ocean acidification when mussels are unable to grow thicker shells. Here, we present the first assessment of mussel shell shape to determine implications for functional protection under ocean acidification.