Cats are not hard to kill, period. Treed cats can be taken with 22 magnums or anything larger. Although powerful, they are fairly lightly constructed - their skin is not thick, nor is their bone structure. They are, however, fast and have long teeth and claws. They can hit hard when they come at you if all their weight is in the air at the time they hit you.
If you see one in the wild it does not mean they are stalking you. If they are stalking you, you won't see it. Mountain Lion do not usually stalk humans but humans can easily be stoopid enuf to traipse through cat country without thinking that they (human) might become the next meal of choice. Jaguar, a South American cat, might have another take on that thought though as they sometimes take humans and small children from jungle villages in Central and South America.
Two cats I have taken were shot with a M19 357 using 125 gn slugs, back in the mid-60s in Colorado. Two other cats, both Central American Jaguar were taken with a 44 magnum (180 gr slug at fast velocities) and a 38 Super using a Charles Askins loading. One cat I let walk, in South Carolina. He was a small male (at least he smelled like one) and when we made eye contact it was because he heard the hammer cock back on my 444; he froze in a perfect broadside and turned his head to look at me and we locked eyes - he was in no position to attack but knew he was 'caught', so I just let'm go - actually, I didn't think he was legal and the game wardens were all over the place.
However, unless maddened by pain, thirst or starvation, a Puma/Mountain Lion is not a threat unless you are a dumb bunny jogging through their territory. If you see/hear one, about the best defense I can think of is a shot in the air or at their feet. They can move fast when they are tryin' to 'get outta town'.....